W/o/w microemulsions for ocular administration

ABSTRACT

Microemulsions are disclosed herein that include a discontinuous internal phase comprising an aqueous solution encompassed within an internal emulsifier; a continuous oil phase encompassing the internal phase; and an external emulsifier encompassing the oil phase. Also disclosed are methods for the use of such microemulsions as drug delivery devices, and methods for treating glaucoma and reducing intraocular pressure.

CROSS REFERENCE

This application claims priority to U.S. provisional patent applicationSer. No. 62/607,429 filed Dec. 19, 2017 and 62/728,564 filed Sep. 7,2018, each incorporated by reference herein in its entirety.

BACKGROUND

Primary open angle glaucoma (POAG) accounts for 90% of glaucoma casesworldwide. It is a leading cause for irreversible blindness. POAG ischaracterized by progressive optic nerve damage arising from apoptoticcell death of retinal ganglion cells. Elevated intraocular pressure(IOP) is one of the most significant risk factors contributing to visualfield loss in this disease. Steady-state IOP is generated by the balanceof aqueous humor (AH) production by the ciliary body (CB) and AHdrainage through the trabecular meshwork (TM; conventional pathway), andto a lesser degree the uveoscleral or nonconventional pathway. Animbalance between the inflow and outflow of AH leads to a change in IOP.Both POAG and IOP are highly heritable. In humans, IOP heritability isestimated to be ˜55%. Moreover, the genetic risk of elevated IOP andPOAG are partially shared, although some loci that are associated withPOAG were not associated with IOP. Identification of gene variants thatmodulate IOP is therefore likely to provide critical insights and newtargets for therapeutic intervention.

Because of the importance of a tightly maintained IOP, its reduction isthe first-line treatment for glaucoma. Despite glaucoma prevalence andits impact on society, current medications do not address the underlyingpathophysiologies that cause elevated IOP, nor do they address geneticvariations related to IOP modulation. Moreover, because of their shorthalf-life and low corneal residence time, they require multiple dailytopical applications, which are associated with poor patient compliance.

SUMMARY

In one aspect, the disclosure provides microemulsions (ME), comprising:

(a) a discontinuous internal phase comprising an aqueous solutionencompassed within an internal emulsifier;

(b) a continuous oil phase encompassing the internal phase; and

(c) an external emulsifier encompassing the oil phase.

In one embodiment, the ME further comprises (d) an aqueous phasesurrounding the external emulsifier. In another embodiment, internalemulsifier is selected from the group consisting of propylene glycolmonocaprylate or any other surfactant with a Hydrophile-LipophileBalance (HLB) value 3-7 and/or propylene glycol ester of any fatty acidsuch as; propylene glycol monocaproate, propylene glycol monocaprylate,propylene glycol monocaprate, propylene glycol monolaurate, propyleneglycol monostearate, propylene glycol monopalmitate, polyethylene glycollauryl ether, polyethylene glycol oleyl ether, polyethylene glycolhexadecyl ether, sorbitan monopalmitate, sorbitan monostearate, sorbitanmonooleate, sorbitan monolaurate, transcutol P, gelucire 50/13, gelucire44/14, gelucire 43/01, any PEG mono-, di- and/or tri-esters of any fattyacid, lecithin, egg lecithin, phosphatidylcholine,phosphatidylethanolamine, phosphatidylinositol, tocopherol or any otherphospholipid, and combinations thereof. In a further embodiment, theinternal emulsifier is selected from the group consisting of caproyl 90,lecithin, and combinations thereof.

In one embodiment, the aqueous solution is selected from the groupconsisting of deionized water, saline, phosphate buffered saline,artificial tears, balanced salt solution. In another embodiment, the oilphase is selected from the group consisting of an oil that consists ofmedium chain triglycerides of caprylic (C₈) and capric (C₁₀) acids, anypure fatty acid ester including but not limited to ethyl, propylisopropyl, and butyl; esters of fatty acids including but not limited tocaproic, caprylic, capric, lauric, palmitic, myristic, or stearic acids,isopropyl myristate, isopropyl palmitate, isopropyl caproate, isopropylcaprylate, ethyl stearate, butyl laurate, and any natural oil includingbut not limited to coconut oil, palm kernel oil, soya bean oil castoroil, cotton seed oil, corn oil, and olive oil; and combinations thereof.In a further embodiment, the oil phase comprises labrafac lipophile WL1349.

In one embodiment, the external emulsifier is selected from the groupconsisting of caprylocaproyl polyoxyl-8 glycerides, macrogolglycerolricinoleate, any other hydrophilic surfactant with aHydrophile-Lipophile Balance (HLB) value between 10-16, polyethyleneglycol mono- and/or di-esters of any fatty acid or fatty acid mixture,propylene glycol or any other alcohol including but not limited toglycerol, polyethylene glycol, ethanol, propanol, and isopropanol; andcombinations thereof. In another embodiment, the external emulsifiercomprises caprylocaproyl polyoxyl-8 glycerides, macrogolglycerolricinoleate, propylene glycol, or combinations thereof.

In one embodiment, the ME contains 0.5-35% w/w aqueous solution, 0.5-95%w/w oil phase, and 5-99% w/w emulsifier. In another embodiment, the MEcontains 10-30% w/w aqueous solution, 20-409 w/w oil phase, and 40-60%w/w emulsifier. In another embodiment, the ME contains at least 0.5% w/waqueous solution, contains at least 1% w/w aqueous solution, contains atleast 2% w/w aqueous solution, contains at least 3% w/w aqueoussolution, contains at least 4% w/w aqueous solution, contains at least5% w/w aqueous solution, contains at least 6% w/w aqueous solution,contains at least 7% w/w aqueous solution, contains at least 8% w/waqueous solution, contains at least 9% w/w aqueous solution, contains atleast 10% w/w aqueous solution, contains at least 11% w/w aqueoussolution, contains at least 12% w/w aqueous solution, contains at least13% w/w aqueous solution, contains at least 14% w/w aqueous solution,contains at least 15% w/w aqueous solution, contains at least 16% w/waqueous solution, contains at least 17% w/w aqueous solution, containsat least 18% w/w aqueous solution, contains at least 19% w/w aqueoussolution, contains at least 20% w/w aqueous solution, contains at least25% w/w aqueous solution, contains at least 30% w/w aqueous solution,contains at least 35% w/w aqueous solution, contains at least 40% w/waqueous solution, contains at least 45% w/w aqueous solution, containsat least 50% w/w aqueous solution, contains at least 55% w/w aqueoussolution, contains at least 60% w/w aqueous solution, contains at least65% w/w aqueous solution, contains at least 70% w/w aqueous solution,contains at least 75% w/w aqueous solution, contains at least 80% w/waqueous solution, contains at least 85% w/w aqueous solution, containsat least 90% w/w aqueous solution, or contains at least 95% w/w aqueoussolution.

In a further embodiment, the aqueous solution comprises a water-solubledrug. In various embodiments, the water soluble drug is selected fromthe group consisting of beta-blockers such as betaxolol and timolol;prostaglandin analogs such as bimatoprost, latanoprost, and travoprost;Alpha-adrenergic agents such as brimonidine tartrate; carbonic anhydraseinhibitors such as brinzolamide, dorzolamide, and acetazolamide; calciumchannel blockers such as nimodipine and pregabalin; asialo,galactosylated, triantennary (NA3)(also known as asialo-, tri-antennarycomplex-type N-glycan), OT-551 hydrochloride(l-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl cyclopropane carboxylicacid ester hydrochloride), brimonidine tartrate, clindamycin,ciprofloxacin, levofloxacin, gatifloxacin, gemifloxacin, olloxacin,triamcinolone, valacyclovir, pyrimethamine, valganciclovir, ganciclovir,acyclovir, foscarnet, prednisolone acetate, diflupednate, triamcinolone,dexamethasone, methotrexate, azathioprine, mycophenolate mofetil,cyclosporine, tacrolimus, cyclophosphamide, ribavirin, bromfenac,ketorolac, nepafenac, lifitegrast, flubiprofen, diclonfenac, ketotifen,nedocromil, phenylephrine, azelastine, epinastine,naphazoline/pheniramine, oloptadine, bepotastine, alacafladine,pemirolast, tetrahydrozoline with or without zinc sulfate, lodoxamide,naphazoline, phenylephrine, cromolyn, emedastine, oxymetazoline,xylometazoline, loratidine, desloratidine, phenylglycine, gabapentin,combinations thereof, or pharmaceutically acceptable salts thereof. Inanother embodiment, the water-soluble drug is selected from the groupconsisting of phenylglycine, gabapentin, pregabalin and ribavirin, or apharmaceutically acceptable salt thereof.

In one embodiment, the aqueous phase comprises a hydrogel. In anotherembodiment, the hydrogel comprises mucoadhesive polymers. In variousfurther embodiments, the mucoadhesive polymers are selected from thegroup consisting of polyacrylic acid derivatives (including but notlimited to CARBOPOL®, such as CARBOPOL® 981), alginic acid and its saltsor derivatives (including but not limited to sodium alginate), chitosanand its derivatives, dextran and its derivatives, pectin and itsderivatives, gelatin and its derivatives, polyvinylpyrroidone and itsderivatives, N-methylpyrrolidone and its derivatives, hyaluronic acidsalts and derivatives thereof, gellan gum and derivatives thereof,xanthan gum and derivatives thereof, agar and derivatives thereof,glycocholic acid and its salts or derivatives, or combinations thereof.In various other embodiments, the mucoadhesive polymers are selectedfrom the group consisting of polyacrylic acid derivatives (including butnot limited to CARBOPOL®, such as CARBOPOL® 981), alginic acid and itssalts or derivatives (including but not limited to sodium alginate),chitosan and its derivatives, or combinations thereof.

In one embodiment, the ME is present as globules between about 1 nm andabout 200 nm in diameter. In another embodiment, the ME is formulated asa topical formulation.

In another aspect, the disclosure provides methods for reducingintraocular pressure (IOP), treating glaucoma, treating age-relatedmacular degeneration (AMD), treating uveitis, and/or treatingconjunctivitis, comprising administering to a subject with intraocularpressure, glaucoma, AMD, uveitis, and/or conjunctivitis an amounteffective to reduce intraocular pressure, treat glaucoma, treat AMD,treat uveitis, and/or treat conjunctivitis of the ME of any embodimentor combinations disclosed herein, wherein the aqueous solution comprisesa water soluble drug capable of reducing IOP, treating glaucoma,treating AMD, treating uveitis, and/or treating conjunctivitis. Invarious embodiments, the water soluble drug capable of reducing IOP,treating glaucoma, treating AMD, treating uveitis, and/or treatingconjunctivitis is selected from the group consisting of beta-blockerssuch as betaxool and timolol; prostaglandin analogs such as bimatoprost,latanoprost, and travoprost; Alpha-adrenergic agents such as brimonidinetartrate; carbonic anhydrase inhibitors such as brinzolamide,dorzolamide, and acetazolamide; calcium channel blockers such asnimodipine and pregabalin; asialo, galactosylated, triantennary(NA3)(also known as asialo-, tri-antennary complex-type N-glycan).OT-551 hydrochloride (1-hydroxy-2,2,6,6-tetramethyl-4-piperidinylcyclopropane carboxylic acid ester hydrochloride), brimonidine tartrate,clindamycin, ciprofloxacin, levofloxacin, gatifloxacin, gemifloxacin,ofloxacin, triamcinolone, valacyclovir, pyrimethamine, valganciclovir,ganciclovir, acyclovir, foscarnet, prednisolone acetate, diflupednate,triamcinolone, dexamethasone, methotrexate, azathioprine, mycophenolatemofetil, cyclosporine, tacrolimus, cyclophosphamide, ribavirin,bromfenac, ketorolac, nepafenac, lifitegrast, flubiprofen, diclonfenac,ketotifen, nedocromil, phenylephrine, azelastine, epinastine,naphazoline/pheniramine, oloptadine, bepotastine, alacaftadine,pemirolast, tetrahydrozoline with or without zinc sulfate, lodoxamide,naphazoline, phenylephrine, cromolyn, emedastine, oxymetazoline,xylometazoline, loratidine, desloratidine, phenylglycine, gabapentin,combinations thereof, or pharmaceutically acceptable salts thereof. Inother embodiments, the water-soluble drug capable of reducing IOP,treating glaucoma, treating AMD, treating uveitis, and/or treatingconjunctivitis is selected from the group consisting of phenylglycine,gabapentin, pregabalin and ribavirin, or a pharmaceutically acceptablesalt thereof.

In one embodiment, the ME is administered to one or both eyes of thesubject. In a further embodiment, the administering is done once perday.

In another aspect, the disclosure provides microemulsions (ME)comprising:

(a) a discontinuous (dispersed) oil phase; and

(b) an emulsifier encompassing the oil phase.

In one embodiment, the ME further comprises (c) a continuous aqueousphase surrounding the emulsifier. In a further embodiment, the MEcomprises an insoluble or sparingly soluble drug in the discontinuousoil phase

In a further aspect, the disclosure provides methods for treatingglaucoma, comprising administering to a subject with glaucoma an amounteffective to treat glaucoma of an inhibitor of Calcium Voltage-GatedChannel Auxiliary Subunit Alpha2delta 1 (CACNA2d1) protein. In oneembodiment, the glaucoma is primary open angle glaucoma (POAG). Inanother aspect, the disclosure provides methods for reducing intraocularpressure, comprising administering to a subject in need thereof anamount effective to treat reduce intraocular pressure of an inhibitor ofCACNA2d1 protein. In one embodiment of each of these aspects, theinhibitor comprises a gabapentanoid or phenylglycine. In one embodiment,the gabapentanoid comprises pregabalin. In a further embodiment, theinhibitor is administered topically. In another embodiment, theinhibitor is administered via eye drops.

DESCRIPTION OF THE FIGURES

FIG. 1: Simple interval map of IOP revealed a single significant eQTL onproximal Chr 5. Cacna2d1 was identified as the top candidate thatmodulates IOP.

FIG. 2: CACNA2D1 is localized to the ciliary body (CB) & trabecularmeshwork (TM).

FIG. 3: Cartoon showing association of CACNA2D1 with the Ca_(v)α1 poreand binding of pregabalin to the CACNA2D1 subunit.

FIG. 4: Pregabalin suspended in hydroxypropyl methylcellulose (HPMC)lowers IOP in B6 mice in a dose-dependent manner, 0.9% is the minimumconcentration that gives maximum effect (n-S).

FIG. 5: Pregabalin (0.9%) suspended in hydroxypropyl methylcellulose(HPMC) lowers IOP by 23% in Dutch belted rabbits (n=5).

FIG. 6: Triphase diagram of Labratec (oil)+transcutol P(surfactant)+H₂O, w/o microemulsion is shown in the shaded region.

FIG. 7: Pseudotriphase diagram of Labrafac (oil)+transcutol P & tween80(surfactant mixture)+H₂O, w/o microemulsion is shown in the shadedregion.

FIG. 8: Triphase diagram of Labrafac (oil)+cremophor EL(surfactant)+H₂O, w/o microemulsion is shown in the shaded region.

FIG. 9: Pseudotriphase diagram of Labrafac (oil)+cremophor EL & tween 80(surfactant mixture)+H₂O, w/o microemulsion is shown in the shadedregion.

FIG. 10: Triphase diagram of Labrafac (oil)+capryol 90 (surfactant)+H₂O,w/o microemulsion is shown in the shaded region.

FIG. 11: Pseudotriphase diagram of Labrafac (oil)+capryol 90 & tween 80(surfactant mixture)+H₂O, w/o microemulsion is shown in the shadedregion.

FIG. 12: Pseudotriphase diagram of Labrafac (oil)+capryol 90 & soybeanlecithin (1:1)(surfactant mixture)+H₂O, w/o microemulsion is shown inthe shaded region.

FIG. 13: Pseudotriphase diagram of Labrafac (oil)+capryol 90 & soybeanlecithin (2:1)(surfactant mixture)+H₂O, w/o microemulsion is shown inthe shaded region.

FIG. 14: Pseudotriphase diagram of Labrafac (oil)+transcutol P & soybeanlecithin (1:1)(surfactant mixture)+H₂O, w/o microemulsion is shown inthe shaded region.

FIG. 15: Cartoon showing composition of multilayered ME hydrogel.

FIG. 16: Pregabalin release profiles from different formulations showthe sustained release behavior of MEs, which is especially clear inCARBOPOL® ME, that gave a steady release rate that lasted for up to 24h.

FIG. 17: Histograms of cytotoxicity pattern of different pregabalinformulations containing pregabalin show the safety of the formulationsto human corneal epithelial cells.

FIG. 18: Histograms of pregabalin formulation viscosity show that theformulation containing CARBOPOL® possesses the highest viscosity value,which allow it to remain on the eye for longer time.

FIG. 19: Histograms of pregabalin formulation mucoadhesion show that theME formulations possess higher mucoadhesion value than the otherformulations.

FIG. 20: Corneal permeability profiles of pregabalin formulations thatdemonstrate that the ME sustain the high corneal permeability ofpregabalin.

FIG. 21: Slit-lamp examination after application of different pregabalinMEs: (a) CARBOPOL®, (b) alginate, or (c) chitosan.

FIG. 22: IOP profiles of Dutch belted rabbits after topical applicationof pregabalin in CARBOPOL® ME at concentrations ranging from 0.1-0.7%(n=5).

FIG. 23: IOP profiles from Dutch belted rabbits after topicalapplication of blank ME, pregabalin in CARBOPOL® gel, and pregabalin inCARBOPOL® ME (n=5).

FIG. 24: IOP profiles from Dutch belted rabbits during a 21-daytachyphylaxis study using pregabalin CARBOPOL® ME (n=5).

FIG. 25: IOP profiles from Dutch belted rabbits during the first 24hours of a 21-day tachyphylaxis study using pregabalin CARBOPOL® ME(n=5).

FIG. 26: IOP profiles from Dutch belted rabbits during the last 24 hoursof a 21-day tachyphylaxis study using pregabalin CARBOPOL® ME (n=5).

FIG. 27: IOP profiles from 86 mice after topical application of 0.9%pregabalin in 2% HPMC viscous eye drops (n=5).

FIG. 28: IOP profiles from B6 mice after topical application of0.9%2-phenylglycine in 2% HPMC viscous eye drops (n=5).

FIG. 29: IOP profiles from B6 mice after topical application of 0.9%gabapentin in 2% HPMC viscous eye drops (n=5).

FIG. 30: IOP profiles from Dutch belted rabbits after topicalapplication of Lumigan, 0.01% dosed at 9 am (n=5).

FIG. 31: IOP profiles from Dutch belted rabbits after topicalapplication of Lumigan, 0.01% dosed at 9 pm (n=5).

FIG. 32: Ribavirin release profiles from different formulations show thesustained release behavior of MEs, which is especially clear inCARBOPOL® ME that gave a steady release rate that lasted for up to 24h.

FIG. 33: Histograms of cytotoxicity of different formulations containingribavirin show the safety of our formulations to human cornealepithelial cells.

FIG. 34: Histograms of viscosity show that the ribavirin formulationcontaining CARBOPOL® possesses the highest viscosity value, which willallow it to remain on the eye for longer time.

FIG. 35: Histograms of formulation mucoadhesion show that the ribavirinCARBOPOL® ME formulation possesses higher mucoadhesion than the otherformulations.

FIG. 36: Corneal permeability profiles of ribavirin formulationsdemonstrate that the MEs increase the corneal permeability of ribavirin.

DETAILED DESCRIPTION

All references cited are herein incorporated by reference in theirentirety.

As used herein. “about” means+/−5% of the recited parameter.

All embodiments of any aspect of the disclosure can be used incombination, unless the context clearly dictates otherwise.

In one aspect microemulsions (ME) are disclosed, comprising

(a) a discontinuous internal phase comprising an aqueous solutionencompassed within an internal emulsifier;

(b) an oil phase encompassing the internal phase; and

(c) an external emulsifier encompassing the oil phase.

As described herein, the inventors have developed novel microemulsions(ME) that can be used, for example, for topical delivery ofwater-soluble drugs. The microemulsions described herein are easy tosynthesize, can be scaled to large batch sizes, are highly biocompatibleand capable of extended drug release.

In one embodiment, the ME further comprise (d) an aqueous phasesurrounding the external emulsifier. In this embodiment, a water solubledrug that is present in the aqueous layer must pass through 2interfaces, the inner w/o interface (i.e.: aqueous solution through theinternal emulsifier) and the outer o/w interface (i.e.: oil phasethrough the external emulsifier), after which it has to diffuse throughthe aqueous phase (including but not limited to a viscous hydrogel) tobe ready for absorption at a site of administration. Because of thisengineering, the time required for the drug to pass through all thesestages is greatly prolonged, allowing for sustained release.

Any suitable hydrophobic internal emulsifier may be used in the MEs. Invarious non-limiting embodiments, the internal emulsifier is selectedfrom the group consisting of propylene glycol monocaprylate or any othersurfactant with an Hydrophile-Lipophile Balance (HLB) value 3-7 and/orpropylene glycol ester of any fatty acid such as; propylene glycolmonocaproate, propylene glycol monocaprylate, propylene glycolmonocaprate, propylene glycol monolaurate, propylene glycolmonostearate, propylene glycol monopalmitate, polyethylene glycol laurylether, polyethylene glycol oleyl ether, polyethylene glycol hexadecylether, sorbitan monopalmitate, sorbitan monostearate, sorbitanmonooleate, sorbitan monolaurate, transcutol P, gelucire 50/13 (mixtureof PEG (MW 1500) mono-, di-, tri-esters of stearic acid), gelucire 44/14(mixture of PEG (MW 1500) mono-, di-, tri-esters of lauric acid),gelucire 43/01 (mixture of PEG (MW 1500) mono-, di-, tri-esters of fattyacids C₈-C₁₈), any PEG mono-, di- and/or tri-esters of any fatty acid,lecithin, egg lecithin, phosphatidycholine, phosphatidylethanolamine,phosphatidylinositol, tocopherol or any other phospholipid, andcombinations thereof.

Capryol 90 is a surfactant with HLB=5. Its chemical name is propyleneglycol monocaprylate (propylene glycol monoester of caprylic acid).Alternatives to propylene glycol monocaprylate may be any othersurfactant with an HLB value 3-7 and/or propylene glycol ester of anyfatty acid such as propylene glycol monocaproate, propylene glycolmonocaprylate, propylene glycol monocaprate, propylene glycolmonolaurate, propylene glycol monostearate, propylene glycolmonopalmitate, polyethylene glycol lauryl ether, polyethylene glycololeyl ether, polyethylene glycol hexadecyl ether, sorbitanmonopalmitate, sorbitan monostearate, sorbitan monooleate, sorbitanmonolaurate, etc.

Labrasol is a hydrophilic surfactant with HLB value 12. It consists of asmall fraction of mono-, di- and triglycerides and mainly polyethyleneglycol-8 (MW 400) mono- and diesters of caprylic and capric acids. Itschemical name is caprylocaproyl polyoxyl-8 glycerides, caprylocaproylmacrogol-8 glycerides or PEG-8 caprylic/capric glycerides. Itsalternatives may be any other hydrophilic surfactant with HLB value(10-14) and/or polyethylene glycol mono- and/or di-esters of any fattyacid.

Cremophor EL is a hydrophilic surfactant with HLB value=14. Its chemicalnames are macrogolglycerol ricinoleate, PEG-35 castor oil, Polyoxyl 35hydrogenated castor oil, or Polyoxyl-35 castor oil. Alternatives may beany other hydrophilic surfactant with HLB value (12-16) and/orpolyethylene glycol mono- and/or di-esters of any fatty acid or fattyacid mixture.

Lecithin is a hydrophobic surfactant with HLB value=4-7. Its chemicalname is2-nonanoyloxy-3-octadeca-9,12-dienoyloxypropoxy)[2-(trimethylazaniumyl)ethyl]phosphinate.It is a mixture of natural phospholipids so its alternatives may be oneof the following: egg lecithin, phosphatidylcholine,phosphatidylethanolamine, phosphatidylinositol, tocopherol or any otherphospholipid.

In one embodiment, the internal emulsifier is selected from the groupconsisting of propylene glycol monocaprylate, lecithin, and combinationsthereof.

Any suitable aqueous solution may be used in the MEs. In variousnon-limiting embodiments, the aqueous solution is selected from thegroup consisting of deionized water, saline, phosphate buffered saline,artificial tears, and balanced salt solution.

Any suitable oil phase may be used in the MEs. In various non-limitingembodiments, the oil phase is selected from the group consisting of anoil that consists of medium chain triglycerides of caprylic (C₈) andcapric (C₁₀) acids, any pure fatty acid ester including but not limitedto ethyl, propyl, isopropyl, and butyl; esters of fatty acids includingbut not limited to caproic, caprylic, capric, lauric, palmitic,myristic, or stearic acids, isopropyl myristate, isopropyl palmitate,isopropyl caproate, isopropyl caprylate, ethyl stearate, butyl laurate,and any natural oil including but not limited to coconut oil, palmkernel oil, soya bean oil, castor oil, cotton seed oil, corn oil, andolive oil, and combinations thereof. In one specific embodiment, the oilphase comprises labrafac lipophile WL1349 (i.e., triglyceride esters ofcaprylic and capric acids).

Any suitable external emulsifier may be used in the MEs. In variousother embodiments, the external emulsifier is selected from the groupconsisting of caprylocaproyl polyoxyl-8 glycerides, macrogolglycerolricinoleate, any other hydrophilic surfactant with Hydrophile-LipophileBalance (HLB) value between 10-16, polyethylene glycol mono- and/ordi-esters of any fatty acid or fatty acid mixture, propylene glycol orany other alcohol including but not limited to glycerol, polyethyleneglycol, ethanol, propanol, and isopropanol; and combinations thereof. Invarious further embodiments, the external emulsifier comprisescaprylocaproyl polyoxyl-8 glycerides, macrogolglycerol ricinoleate,propylene glycol, or combinations thereof.

Any suitable combinations of the various components of the MEs of thedisclosure may be used. In one embodiment, the ME contains 0.5-35% w/waqueous solution, 0.5-95% w/w oil phase, and 5-99% w/w emulsifier (i.e.:internal emulsifier+external emulsifier). In another embodiment, the MEcontains 10-30% w/w aqueous solution, 20-40% w/w oil phase, and 40-60%w/w emulsifier. In a further embodiment, the ME contains about 20% w/waqueous solution, about 30% w/w oil phase, and about 50% w/w emulsifier.In various further embodiments, the ME contains at least 0.5% w/waqueous solution, contains at least 1% w/w aqueous solution, contains atleast 2% w/w aqueous solution, contains at least 3% w/w aqueoussolution, contains at least 4% w/w aqueous solution, contains at least5% w/w aqueous solution, contains at least 6% w/w aqueous solution,contains at least 7% w/w aqueous solution, contains at least 8% w/waqueous solution, contains at least 9% w/w aqueous solution, contains atleast 10% w/w aqueous solution, contains at least 11% w/w aqueoussolution, contains at least 12% w/w aqueous solution, contains at least13% w/w aqueous solution, contains at least 14% w/w aqueous solution,contains at least 15% w/w aqueous solution, contains at least 16% w/waqueous solution, contains at least 17% w/w aqueous solution, containsat least 18% w/w aqueous solution, contains at least 19% w/w aqueoussolution, contains at least 20% w/w aqueous solution, contains at least25% w/w aqueous solution, contains at least 30% w/w aqueous solution,contains at least 35% w/w aqueous solution, contains at least 40% w/waqueous solution, contains at least 45% w/w aqueous solution, containsat least 50% w/w aqueous solution, contains at least 55% w/w aqueoussolution, contains at least 60% w/w aqueous solution, contains at least65% w/w aqueous solution, contains at least 70% w/w aqueous solution,contains at least 75% w/w aqueous solution, contains at least 80% w/waqueous solution, contains at least 85% w/w aqueous solution, containsat least 90% w/w aqueous solution, or contains at least 95% w/w aqueoussolution.

In various embodiments, the external emulsifier is present in a ratiobetween about 10:1 and about 2:1 relative to the internal emulsifier. Invarious further embodiments, the external emulsifier is present in aratio between about 9:1 and about 2:1, between about 8:1 and about 2:1,between about 7:1 and about 2:1, between about 6:1 and about 2:1,between about 5:1 and about 2:1, between about 4:1 and about 2:1,between about 3:1 and about 2:1, between about 10:1 and about 2.5:1,between about 9:1 and about 2.5:1, between about 8:1 and about 2.5:1,between about 7:1 and about 2.5:1, between about 6:1 and about 2.5:1,between about 5:1 and about 2.5:1, between about 4:1 and about 2.5:1,between about 3:1 and about 2.5:1, between about 10:1 and about 3:1relative to the internal emulsifier, between about 9:1 and about 3:1,between about 8:1 and about 3:1, between about 7:1 and about 3:1,between about 6:1 and about 3:1, between about 5:1 and about 3:1,between about 4:1 and about 3:1, between about 10:1 and about 4:1relative to the internal emulsifier, between about 9:1 and about 4:1,between about 8:1 and about 4:1, between about 7:1 and about 4:1,between about 6:1 and about 4:1, between about 5:1 and about 4:1,between about 10:1 and about 5:1 relative to the internal emulsifier,between about 9:1 and about 5:1, between about 8:1 and about 5:1,between about 7:1 and about 5:1, between about 6:1 and about 5:1,relative to the internal emulsifier.

In one embodiment, the aqueous solution comprises a water solubletherapeutic. Any suitable water soluble therapeutic may be incorporatedin the aqueous solution, including but not limited to beta-blockers suchas betaxolol and timolol; prostaglandin analogs such as bimatoprost,latanoprost, and travoprost; Alpha-adrenergic agents such as brimonidinetartrate; carbonic anhydrase inhibitors such as brinzolamide,dorzolamide, and acetazolamide; calcium channel blockers such asnimodipine and pregabalin; asialo, galactosylated, triantennary (NA3)(also known as asialo-, tri-antennary complex-type N-glycan), OT-551hydrochloride (1-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl cyclopropanecarboxylic acid ester hydrochloride), brimonidine tartrate, clindamycin,ciprofloxacin, levofloxacin, gatifloxacin, gemifloxacin, ofloxacin,triamcinolone, valacyclovir, pyrimethamine, valganciclovir, ganciclovir,acyclovir, foscarnet, prednisolone acetate, diflupednate, triamcinolone,dexamethasone, methotrexate, azathioprine, mycophenolate mofetil,cyclosporine, tacrolimus, cyclophosphamide, ribavirin, bromfenac,ketorolac, nepafenac, lifitegrast, flubiprofen, diclonfenac, ketotifen,nedocromil, phenylephrine, azelastine, epinastine,naphazoline/pheniramine, oloptadine, bepotastine, alacaftadine,pemirolast, tetrahydrozoline with or without zinc sulfate, lodoxamide,naphazoline, phenylephrine, cromolyn, emedastine, oxymetazoline,xylometazoline, loratidine, desloratidine, phenylglycine, gabapentin, orcombinations thereof. In specific embodiments, the water-soluble drug isselected from the group consisting of phenylglycine, gabapentin,pregabalin and ribavirin, or a pharmaceutically acceptable salt thereof.

In another embodiment, the aqueous phase comprises a hydrogel (i.e.: agel or swollen network structured polymer matrix in which the liquidcomponent is water or aqueous solution, emulsion or suspension). In oneembodiment, the hydrogel comprises mucoadhesive polymers. Any suitablemucoadhesive polymers may be used, including but not limited topolyacrylic acid derivatives (including but not limited to CARBOPOL®,such as CARBOPOL® 981), alginic acid and its salts or derivatives(including but not limited to sodium alginate), chitosan and itsderivatives, dextran and its derivatives, pectin and its derivatives,gelatin and its derivatives, polyvinylpyrrolidone and its derivatives,N-methylpyrrolidone and its derivatives, hyaluronic acid salts andderivatives thereof, gellan gum and derivatives thereof, xanthan gum andderivatives thereof, agar and derivatives thereof, glycocholic acid andits salts or derivatives, or combinations thereof. In specificembodiments, the mucoadhesive polymers are selected from the groupconsisting of polyacrylic acid derivatives (including but not limited toCARBOPOL®, such as CARBOPOL® 981), alginic acid and its salts orderivatives (including but not limited to sodium alginate), chitosan andits derivatives, or combinations thereof.

The ME may be formulated for any suitable route of administration (i.e.:orally, topically, intranasally, etc.), in dosage unit formulations ofwater soluble therapeutic loaded in the ME. The formulation may includeany other components suitable for a desired administrative route,including but not limited to conventional pharmaceutically acceptablecarriers, adjuvants, and vehicles. In one embodiment, the ME isformulated as a topical formulation, such as for delivery to the eye.

The MEs disclosed herein may be provided as ME globules (i.e., drops).ME globules may be of any suitable size, in one embodiment, the MEglobule is between about 1 nm and about 200 nm in diameter. In variousfurther embodiments, ME globules are between about 1 nm and about 150nm, about 1 nm and about 100 nm, about 1 nm and about 50 urn, about 1 nmand about 20 nm, about 1 nm and about 18 nm, about 1 nm and about 17 nm,about 5 nm and about 200 nm, about 5 nm and about 150 nm, about 5 nm andabout 100 nm, about 5 nm and about 50 nm, about 5 nm and about 20 nm,about 5 nm and about 18 nm, about 5 nm and about 17 nm in diameter. Invarious further embodiments, the ME globules are about 1 nm, about 2 nm,about 3 nm, about 4 nm, about 5 nm, about 6 nm, about 7 nm, about 8 nm,about 9 nm, about 10 nm, about 15 nm, about 20 nm, about 25 nm, about 30nm, about 35 nm, about nm, about 45 nm, about 50 nm, about 55 nm, about60 nm, about 65 nm, about 70 nm, about 75 nm, about 80 nm, about 90 nm,about 95 nm, about 100 nm, about 110 nm, about 120 nm, about 130 nm,about 140 nm, about 150 nm, about 160 nm, about 170 nm, about 180 nm,about 190 or about 200 nm in diameter. In other embodiments, the MEglobules are at least about 1 nm, at least 2 nm, at least 3 nm, at least4 nm, at least 5 nm, at least 6 nm, at least 7 nm, at least 8 nm, atleast 9 nm, at least 10 nm, at least 15 nm, at least 20 nm, at least 25nm, at least 30 nm, at least 35 nm, at least 40 nm, at least 45 nm, atleast 50 nm, at least 55 nm, at least 60 nm, at least 65 nm, at least 70nm, at least 75 nm, at least 80 nm, at least 90 nm, at least 95 nm, atleast 100 nm, at least 110 nm, at least 120 nm, at least 130 nm, atleast 140 nm, at least 150 nm, at least 160 nm, at least 170 nm, atleast 180 nm, at least 190 or at least 200 nm in diameter.

In another aspect is provided methods for treating an eye diseasecomprising administering to a subject in need thereof an amounteffective to treat the eye disease of the ME of any embodiment orcombination of embodiments described herein, wherein the aqueoussolution comprises a water soluble therapeutic capable of treating theeye disease. In various embodiments, the methods are for reducingintraocular pressure (IOP), treating glaucoma, treating age-relatedmacular degeneration (AMD), treating uveitis, and/or treatingconjunctivitis, comprising administering to a subject with elevatedintraocular pressure, glaucoma, AMD, uveitis, and/or conjunctivitis anamount effective to reduce intraocular pressure, treat glaucoma, treatAMD, treat uveitis, and/or treat conjunctivitis of the ME of anyembodiment or combination of embodiments described herein, wherein theaqueous solution comprises a water soluble therapeutic capable ofreducing IOP, treating glaucoma, treating AMD, treating uveitis, and/ortreating conjunctivitis. In various embodiments, the water solubletherapeutic capable of reducing IOP, treating glaucoma, treating AMD,treating uveitis, and/or treating conjunctivitis is selected from thegroup consisting of beta-blockers such as betaxolol and timolol;prostaglandin analogs such as bimatoprost, latanoprost, and travoprost;Alpha-adrenergic agents such as brimonidine tartrate; carbonic anhydraseinhibitors such as brinzolamide, dorzolamide, and acetazolamide; calciumchannel blockers such as nimodipine and pregabalin; asialo,galactosylated, triantennary (NA3)(also known as asialo-, tri-antennarycomplex-type N-glycan), OT-551 hydrochloride(1-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl cyclopropane carboxylicacid ester hydrochloride), brimonidine tartrate, clindamycin,ciprofloxacin, levofloxacin, gatifloxacin, gemifloxacin, ofloxacin,triamcinolone, valacyclovir, pyrimethamine, valganciclovir, ganciclovir,acyclovir, foscarnet, prednisolone acetate, diflupednate, triamcinolone,dexamethasone, methotrexate, azathioprine, mycophenolate mofetil,cyclosporine, tacrolimus, cyclophosphamide, ribavirin, bromfenac,ketorolac, nepafenac, lifitegrast flubiprofen, diclonfenac, ketotifen,nedocromil, phenylephrine, azelastine, epinastine,naphazoline/pheniramine, oloptadine, bepotastine, alacaftadine,pemirolast, tetrahydrozoline with or without zinc sulfate, lodoxamide,naphazoline, phenylephrine, cromolyn, emedastine, oxymetazoline,xylometazoline, loratidine, deslortidine, phenylglycine, gabapentin, orcombinations thereof. In specific embodiments, the water soluble drugcapable of reducing IOP, treating glaucoma, treating AMD, treatinguveitis, and/or treating conjunctivitis is selected from the groupconsisting of phenylglycine, gabapentin, pregabalin and ribavirin, or apharmaceutically acceptable salt thereof. In one specific embodiment,the water soluble drug capable of reducing IOP, treating glaucoma,treating AMD, treating uveitis, and/or treating conjunctivitis ispregabalin, and the pregabalin is present in the ME at between about0.2% to about 2% of the ME % w/w; in various further embodiments, thepregabalin is present in the ME at between about 0.2% to about 1.5%,between about 0.2% to about 1%, between about 2% to about 0.75%, betweenabout 0.3% to about 2%, between about 0.3% to about 1.5%, between about0.3% to about 1%, between about 0.3% to about 0.75%, between about 0.4%to about 2%, between about 0.4% to about 1.5%, between about 0.4% toabout 1%, between about 0.4% to about 0.75%, between about 0.5% to about2%, between about 0.5% to about 1.5%, between about 0.5% to about 1%,between about 0.5% to about 0.75%, between about 0.2% to about 0.6%,between about 0.3% to about 0.6%, between about 0.4% to about 0.6%,between about 0.5% to about 0.6%, about 0.2%, about 0.3%, about 0.4%,about 0.5%, or about 0.6% of the ME % w/w. The MEs described herein areexcellent drug delivery systems for any water-soluble therapeuticcandidate.

In other aspects of this embodiment, a water-soluble drug disclosedherein is used to reduce IOP and/or treat glaucoma (including POAG),AMD, uveitis, and/or conjunctivitis in a patient suffering from one ormore of these syndromes by, e.g., at least 10%, at least 15%, at least20%, at least 25%, at least 30%, at least 35%, at least 40%, at least45%, at least 50%, at least 55%, at least 60%, at least 65%, at least70%, at least 75%, at least 80%, at least 85%, at least 90% or at least95%. In yet other aspects of this embodiment, a water-soluble drugdisclosed herein reduces IOP and/or treats glaucoma, AMD, uveitis,and/or conjunctivitis in a patient suffering from one of these syndromesfrom, e.g., about 5% to about 100%, about 10% to about 100%, about 20%to about 100%, about 30% to about 100%, about 40% to about 100%, about50% to about 100%, about 60% to about 100%, about 70% to about 100%,about 80% to about 100%, about 10% to about 90%, about 20% to about 90%,about 30% to about 90%, about 40% to about 90%, about 50% to about 90%,about 60% to about 90%, about 70% to about 90%, about 10% to about 80%,about 20% to about 80%, about 30% to about 80%, about 40% to about 80%,about 50% to about 80%, or about 60% to about 80%, about 10% to about70%, about 20% to about 70%, about 30% to about 70%, about 40% to about70%, or about 50% to about 70%.

An ME disclosed herein may comprise a water-soluble drug in an amountsufficient to allow customary administration to an individual. Inaspects of this embodiment, a ME disclosed herein may include, e.g., atleast 0.3% w/w, at least 0.4% w/w, 0.5% w/w, at least 0.6% w/w, at least0.7% w/w, at least 0.8% w/w, at least 0.9% w/w, at least 1.0% w/w, atleast 1.1% w/w, at least 1.2% w/w of a water-soluble drug. In yet otheraspects of this embodiment, a ME disclosed herein may include, e.g.,about 0.3% w/w to about 1.2% w/w, about 0.3% w/w to about 1.1% w/w,about 0.3% w/w to about 1.0% w/w, about 0.3% w/w to about 0.9% w/w,about 0.3% w/w to about 0.8% w/w, about 0.4% w/w to about 1% w/w, about0.4% w/w to about 0.9% w/w, about 0.4% w/w to about 0.8% w/w, about 0.4%w/w to about 0.7% w/w, about 0.5% w/w to about 1.0% w/w, about 0.5% w/wto about 0.9% w/w, about 0.5% w/w to about 0.8% w/w, about 0.5% w/w toabout 0.7% w/w, about 0.55% w/w to about 0.8% w/w, or about 0.55% w/w toabout 0.7% w/w of a water-soluble drug.

The final concentration of a water-soluble drug disclosed herein in a MEdisclosed herein may be of any concentration desired. In an aspect ofthis embodiment, the final concentration of a water-soluble drug in a MEmay be a therapeutically effective amount. In other aspects of thisembodiment, the final concentration of a water-soluble drug in a ME maybe, e.g., at least 0.3% w/w, at least 0.4% w/w, 0.5% w/w, at least 0.6%w/w, at least 0.7% w/w, at least 0.8% w/w, at least 0.9% w/w, at least1.0% w/w, at least 1.1% w/w, at least 1.2% w/w, in other aspects of thisembodiment, the concentration of a water-soluble drug disclosed hereinin a ME may be, e.g., at most 0.3% w/w, at most 0.4% w/w, at most 0.5%w/w, at most 0.6% w/w, at most 0.7% w/w, at most 0.8% w/w, at most 0.9%w/w, at most 1.0% w/w, at most 1.1% w/w, or at most 1.2% w/w. In otheraspects of this embodiment, the final concentration of a water-solubledrug in a ME may be in a range of, e.g., bout 0.3% w/w to about 1.2%w/w, about 0.3% w/w to about 1.1% w/w, about 0.3% w/w to about 1.0% w/w,about 0.3% w/w to about 0.9% w/w, about 0.3% w/w to about 0.8% w/w,about 0.4% w/w to about 1% w/w, about 0.4% w/w to about 0.9% w/w, about0.4% w/w to about 0.8% w/w, about 0.4% w/w to about 0.7% w/w, about 0.5%w/w to about 1.0% w/w, about 0.5% w/w to about 0.9% w/w, about 0.5% w/wto about 0.8% w/w, about 0.5% w/w to about 0.7% w/w, about 0.55% w/w toabout 0.8% w/w, or about 0.55% w/w to about 0.7% w/w.

As used herein, “treat” or “treating” means accomplishing one or more ofthe following: (a) reducing the severity of the disorder; (b) limitingor preventing development of symptoms characteristic of the disorder(s)being treated; (c) inhibiting worsening of symptoms characteristic ofthe disorder(s) being treated; (d) limiting or preventing recurrence ofthe disorder(s) in patients that have previously had the disorder(s);and (e) limiting or preventing recurrence of symptoms in patients thatwere previously symptomatic for the disorder(s). Certain embodiments ofthe present specification disclose, in part, treating an individualsuffering from IOP, glaucoma, AMD, uveitis, and/or conjunctivitis. Inthese embodiments, treating may refer to reducing or eliminating in anindividual a clinical symptom of IOP, glaucoma, AMD, uveitis, and/orconjunctivitis; or delaying or preventing in an individual the onset ofa clinical symptom of IOP, glaucoma, AMD, uveitis, and/orconjunctivitis. For example, the term “treating” can mean reducing asymptom of a condition characterized by a IOP, glaucoma, AMD, uveitis,and/or conjunctivitis, by, e.g., at least 20%, at least 25%, at least30%, at least 35%, at least 40%, at least 45%, at least 50%, at least55%, at least 60%, at least 65%, at least 70%, at least 75%, at least80%, at least 85%, at least 90% at least 95%, or at least 100%. Theactual symptoms associated with IOP, glaucoma, AMD, uveitis, and/orconjunctivitis are well known and can be determined by a person ofordinary skill in the art by taking into account various factorsassociated with each of these syndromes. Those of skill in the art willknow the appropriate symptoms or indicators associated with IOP,glaucoma, AMD, uveitis, and/or conjunctivitis and will know how todetermine if an individual is a candidate for treatment as disclosedherein.

In various embodiments, a therapeutically effective amount of awater-soluble drug disclosed herein reduces a symptom associated withIOP, glaucoma, AMD, uveitis, and/or conjunctivitis by, e.g., at least10%, at least 15%, at least 20%, at least 25%, at least 30%, at least35%, at least 40%, at least 45%, at least 50%, at least 55%, at least60%, at least 65%, at least 70%, at least 75%, at least 80%, at least85%, at least 90%, at least 95% or at least 100%. In other embodiments,a therapeutically effective amount of a water-soluble drug disclosedherein reduces a symptom associated with IOP, glaucoma, AMD, uveitis,and/or conjunctivitis by, e.g., at most 10%, at most 15%, at most 20%,at most 25%, at most 30%, at most 35%, at most 40%, at most 45%, at most50%, at most 55%, at most 60%, at most 65%, at most 70%, at most 75%, atmost 80%, at most 85%, at most 90%, at most 95% or at most 100%. In yetother embodiments, a therapeutically effective amount of a water-solubledrug disclosed herein reduces a symptom associated with IOP, glaucoma,AMD, uveitis, and/or conjunctivitis by, e.g., about 10% to about 100%,about 10% to about 90%, about 10% to about 80%, about 10% to about 70%,about 10% to about 60%, about 10% to about 50%, about 10% to about 40%,about 20% to about 100%, about 20% to about 90%, about 20% to about 80%,about 20, to about 20%, about 20% to about 60%, about 20% to about 50%,about 20% to about 40%, about 30% to about 100%, about 30% to about 90%,about 30% to about 80%, about 30% to about 70%, about 30% to about 60%,or about 30% to about 50%.

The therapeutics (such as the MEs) for use in the methods disclosedherein may be administered as deemed appropriate by attending medicalpersonnel. In one embodiment, the therapeutics for use in the methodsdisclosed herein (such as the ME) are administered to one or both eyesof the subject. In another embodiment, the administering is done onceper day. Dosing can be single dosage or cumulative (serial dosing), andcan be readily determined by one skilled in the art. For instance,treatment of IOP, glaucoma, AMD, uveitis, and/or conjunctivitis maycomprise a one-time administration of an effective dose of a MEcontaining a water-soluble drug disclosed herein. Alternatively,treatment of IOP, glaucoma, AMD, uveitis, and/or conjunctivitis maycomprise multiple administrations of an effective dose of a MEcontaining a water-soluble drug carried out over a range of timeperiods, such as, e.g., once daily, twice daily, trice daily, once everyfew days, or once weekly. The timing of administration can vary fromindividual to individual, depending upon such factors as the severity ofan individual's symptoms. For example, an effective dose of a MEcontaining a water-soluble drug disclosed herein can be administered toan individual once daily for an indefinite period of time, or until theindividual no longer requires therapy. A person of ordinary skill in theart will recognize that the condition of the individual can be monitoredthroughout the course of treatment and that the effective amount of a MEcontaining a water-soluble drug disclosed herein that is administeredcan be adjusted accordingly.

In various embodiments, a sustained release water-soluble drug deliveryplatform releases a water-soluble drug disclosed herein withsubstantially zero order release kinetics over a period of, e.g., about7 days after administration, about 15 days after administration, about30 days after administration, about 45 days after administration, about60 days after administration, about 75 days after administration, orabout 90 days after administration. In other embodiments, a sustainedrelease water-soluble drug delivery platform releases a water-solubledrug disclosed herein with substantially zero order release kineticsover a period of, e.g., at least 7 days after administration, at least15 days after administration, at least 30 days after administration, atleast 45 days after administration, at least 60 days afteradministration, at least 75 days after administration, or at least 90days after administration.

In a further embodiment, a water-soluble drug of the present inventionand its derivatives have half-lives of 2 hours, 3 hours, 4 hours, 5hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 1 hours, 12 hours,13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20hours, 21 hours, 22 hours, 23 hours, 1 day, 2 days, 3 days, 4 days, 5days, 6 days, 7 days, 1 week, 2 weeks, 3 weeks, 4 weeks, one month, twomonths, three months, four months or more.

In an embodiment, the period of administration of a therapeutic for thetreatment of IOP, glaucoma, AMD, uveitis, and/or conjunctivitis is for 1day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11months, 12 months, or more. In a further embodiment, a period of duringwhich administration is stopped between period of administration is for1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days,10 days, 1 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11months, 12 months, or more.

In various embodiments, a water-soluble drug delivery platform releasesa therapeutic disclosed herein with substantially zero order releasekinetics over a period of, e.g. about 1 day after administration, about2 days after administration, about 3 days after administration, about 4days after administration, about 5 days after administration, or about 6days after administration. In other aspects of this embodiment, awater-soluble drug delivery platform releases a therapeutic disclosedherein with substantially zero order release kinetics over a period of,e.g., at most 1 day after administration, at most 2 days afteradministration, at most 3 days after administration, at most 4 daysafter administration, at most 5 days after administration, or at most 6days after administration.

In various embodiments, a therapeutically effective amount of a MEcontaining a water-soluble drug disclosed herein reduces internalpressure within the eye of an individual by, e.g., at least 10%, atleast 15%, at least 20%, at least 25%, at least 30%, at least 35%, atleast 40%, at least 45%, at least 50%, at least 55%, at least 60%, atleast 65%, at least 70%, at least 75%, at least 80%, at least 85%, atleast 90%, at least 95% or at least 100%. In other aspects of thisembodiment, a therapeutically effective amount of a ME containing awater-soluble drug disclosed herein reduces internal pressure within theeye in an individual by, e.g., at most 10%, at most 15%, at most 20%, atmost 25%, at most 30%, at most 35%, at most 40%, at most 45%, at most50%, at most 55%, at most 60%, at most 65%, at most 70%, at most 75%, atmost 80%, at most 85%, at most 90%, at most 95% or at most 100%. In yetother aspects of this embodiment, a therapeutically effective amount ofa Me containing a water-soluble drug disclosed herein reduces internalpressure within the eye in an individual by, e.g., about 10% to about100%, about 10% to about 90%, about 10% to about 80%, about 10% to about70%, about 10% to about 60%, about 10% to about 50%, about 10% to about40%, about 20% to about 100%, about 20% to about 90%, about 20% to about800%, about 20% to about 20%, about 20% to about 60%, about 20% to about50%, about 20% to about 40%, about 30% to about 100%, about 30% to about90%, about 30% to about 80%, about 30% to about 70%, about 30% to about60%, or about 30% to about 50%.

As used herein, the term “subject”, “individual,” or “patient,” usedinterchangeably, refer to any animal, including mammals, such as mice,rats, other rodents, rabbits, dogs, cats, birds, swine, horses,livestock (e.g., pigs, sheep, goats, cattle), primates or humans. Inspecific embodiments, the subject, individual, or patient is a human. Apharmaceutical composition that includes a ME and a water-soluble drugis administered to a subject. Typically, any subject who is a candidatefor treatment is a candidate with some form of IOP, glaucoma, AMD,uveitis, and/or conjunctivitis. Pre-operative evaluation typicallyincludes routine history and physical examination in addition tothorough informed consent disclosing all relevant risks and benefits ofthe procedure.

The therapeutic-containing MEs for use in the methods disclosed hereincan be formulated for and administered via any suitable route, includingbut not limited to oral, intravenous, intravaginal, intra-anal,subcutaneous, intracranial, topical, intramuscular, enteral orparenteral routes of administration. In specific embodiments, thetherapeutic-containing MEs can be formulated for and administered viatopical administration for ocular or optic application (including butnot limited to being formulated as eye drops), intranasaladministration, orally for different systemic diseases, transdermalapplication for systemic diseases and topically for different skindisorders. The MEs described herein can also be used as a drug deliverysystem to incorporate one or more water-soluble compounds of any type,including but not limited to small molecules and peptides, in a singleME.

Preparation of the ME may be carried out under any suitable conditionsas appropriate for an intended use. In one non-limiting embodiment,preparation of the MW may be carried out at room temperature, in orderto allow a water-soluble drug to dissolve fully in the pharmaceuticallyacceptable solvent. However, in other embodiments of the method,preparation of the ME may be carried out at a temperature that isgreater than room temperature. In aspects of this embodiment,preparation of the ME may be carried out at a temperature that is, e.g.,greater than 21° C., greater than 25° C., greater than 30° C., greaterthan 35° C. or greater than 37° C., greater than 40° C., greater than42° C., greater than 45° C., greater than 50° C., greater than 55° C.,or greater than 60° C. In aspects of this embodiment, preparation of theME may be carried out at a temperature that is between, e.g., about 20°C. to about 30° C., about 25° C. to about 35° C., about 30° C. to about40° C., about 35° C. to about 45° C., about 40° C. to about 50° C.,about 45° C. to about 55° C., or about 50° C. to about 60° C. In certaincases, preparation of the ME may be carried out at temperatures belowroom temperature, in order to allow a therapeutic to dissolve fully insolvent. However, in other embodiments of the method, preparation of theME may be carried out at a temperature that is less than roomtemperature, e.g., less than 10° C., greater than 5° C., greater than 0°C., greater than −10° C. or greater than −20° C.

In an embodiment, a water-soluble drug for use with an ME is pregabalin.

In another aspect are provided methods for treating glaucoma or reducingIOP, comprising administering to a subject in need thereof an amounteffective to treat glaucoma or reduce IOP of an inhibitor of CalciumVoltage-Gated Channel Auxiliary Subunit Alpha2Delta1 (CACNA2D) protein.In one embodiment, the methods are to treat glaucoma; in one suchembodiment, the glaucoma is primary open angle glaucoma (POAG). In oneembodiment, the inhibitor comprises a gabapentanoid, phenylglycine, or apharmaceutically acceptable salt thereof. In another embodiment, thegabapentanoid comprises pregabalin, or a pharmaceutically acceptablesalt thereof.

As used herein, the phrase “pharmaceutically acceptable salt” refers toboth pharmaceutically acceptable acid and base addition salts andsolvates. Such pharmaceutically acceptable salts may be any saltssuitable for san intended use, including but not limited to salts ofacids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic,formic, toluenesulfonic, methanesulfonic, nitric, benzoic, citric,tartaric, maleic, hydroiodic, alkanoic such as acetic,HOOC—(CH₂)_(n)—COOH where n is 0-4, and the like. Non-toxicpharmaceutical base addition salts include salts of bases such assodium, potassium, calcium, ammonium, and the like. Those skilled in theart will recognize a wide variety of non-toxic pharmaceuticallyacceptable addition salts.

As used here, a subject “in need thereof” refers to a subject that hasthe disorder or disease to be treated or is predisposed to or otherwiseat risk of developing the disease or disorder.

In one non-limiting example, the MEs may comprise or consist of thefollowing components:

(a) a primary water-in-oil (w/o) phase constituting between about 0.1%and about 40% of the formulation, wherein the w/o phase comprises:

-   -   (i) water at a concentration of between 0% and about 7% w/w of        the formulation;    -   (ii) oil at a concentration of between about 6% and about 13%        w/w of the formulation;    -   (iii) capryol 90 at a concentration of between about 1% and        about 13% w/w of the formulation; and    -   (iv) lecithin at a concentration of between about 1% and about        13% w/w of the formulation; and

(b) an external aqueous phase constituting 50-99.9% of the formulation,wherein the external aqueous phase comprises:

-   -   (i) labrasol at a concentration of between about 0.1% and about        25% w/w of the formulation,    -   (ii) cremophor EL at a concentration of between about 0.1% and        about 25% w/w of the formulation;    -   (iii) propylene glycol at a concentration of between 0% and        about 45% w/w of the formulation; and    -   (iv) water at a concentration of between about 10% and about        99.7% w/w of the formulation,

In another non-limiting example, the MEs may comprise or consist of thefollowing components:

(a) a primary water-in-oil (w/o) phase constituting between about 0.1%and about 40% of the formulation, wherein the w/o phase comprises:

-   -   (i) water at a concentration of between 2% and about 7% w/w of        the formulation;    -   (ii) oil at a concentration of between about 6% and about 9% w/w        of the formulation;    -   (iii) Capryol 90 at a concentration of between about 3% and        about 9% w/w of the formulation; and    -   (iv) lecithin at a concentration of between about 3% and about        9% w/w of the formulation; and

(b) an external aqueous phase constituting 50-99.9% of the formulation,wherein the external aqueous phase comprises:

-   -   (i) labrasol at a concentration of between about 5% and about        9.5% w/w of the formulation;    -   (ii) Cremophor EL at a concentration of between about 5% and        about 9.5% w/w of the formulation;    -   (iii) propylene glycol at a concentration of between 5% and        about 25% w/w of the formulation; and    -   (iv) water at a concentration of between about 30% and about 56%        w/w of the formulation,

In another aspect are provided microemulsions designed as a drugdelivery system for water-insoluble and sparingly-water soluble drugsmolecules. In these embodiments, the MEs are the same as describedabove, but lack the internal aqueous phase and internal emulsifier.Thus, in this embodiment the ME comprises:

(a) a discontinuous (dispersed) oil phase: and

(b) an emulsifier encompassing the oil phase.

In one embodiment, the ME further comprises (c) a continuous aqueousphase surrounding the emulsifier. In this embodiment, the oily drugsolution is emulsified in the bioadhesive aqueous phase (such as ahydrogel as described herein) that contains a hydrophilic emulsifier(i.e. emulsifier with high HLB value).

In a further embodiment, the ME comprises an insoluble or sparinglysoluble drug in the discontinuous oil phase.

All embodiments disclosed above for the MEs can be used in this aspectas well, unless the context clearly dictates otherwise.

Examples Cacna2d1 is Identified as an IOP-Modulating Gene

We systematically measured IOP across a large subset of the BXD familyin multiple age cohorts. Using stringent stepwise refinement based onexpression quantitative trait locus (QTL) mapping, correlation analyses(direct and partial Pearson test), and the analysis of single-nucleotidepolymorphisms (SNPs), we are able to identify a candidate gene thatmodulates IOP, and using mouse and human genetic data, we can validatethe candidate gene. To determine the candidate gene variants thatmodulate IOP within the Chr 5 locus, we used the following stringentcriteria): (1) the gene is located within the confidence interval of thepeak eQTL; (2) the gene has cis-modulation; (3) the expression level ofthe gene across BXD strains is significantly correlated with elevatedIOP using both linear correlation and partial Pearson correlationanalyses; (4) the gene functions within a network that could explain itsrole in modulating IOP; (5) the gene has sequence variants betweenparental strains at/near the region of the gene; (6) the gene isexpressed in the eye and localized to an area associated with modulationof IOP; (7) the gene is associated with human POAG and/or elevated IOPeither through GWAS or standard linkage studies; and (8) the gene has abiological association with glaucoma or its treatment Within the QTLpeak at Chr 5, there were 25 positional gene candidates that werecis-regulated. Using our above criteria, calcium channel,voltage-dependent, α2δ1subunit (Cacna2d1) emerged as the single bestpositional candidate (r=0.440; P=0.0003)(FIG. 1).

To further test Cacna2d1 as a candidate IOP modulating gene, weperformed immunohistochemistry to determine the localization pattern ofCACNA2D1 in healthy mouse and human donor eyes. In the mouse eye,CACNA2D1 is prominently localized to the TM, CB, and ciliary muscle(CM). CACNA2D1 was observed in a punctuate pattern throughout the TM andSchlemm's canal. In the CB, CACNA2D1 was highly expressed in thenon-pigmented epithelium. Weak labeling was present in the CM (FIG. 2).

We showed that CACNA2D1 is expressed in both CB and TM. It is alsomodestly present in the CM. Based upon these collective data, it appearsthat CACNA2D1 regulates IOP (FIG. 3). Pregabalin, or other gabapentinoiddrugs, binds to the CACNA2D1 subunit of the calcium channel. The bindingof the drug mitigates the flux of calcium through the α1 pore of thecalcium channel, reducing the level of intracellular calcium, SinceCacna2d1 modulates IOP, pregabalin, a gabapentinoid drug with highspecificity for CACNA2D1, was evaluated for its ability to affect IOP.Pregabalin ophthalmic eye drops [(pregabalin suspended in hydroxypropylmethylcellulose (HPMC)] reduce IOP in mice in a dose-dependent mannerfrom 0.3-1.2% (FIG. 4). Drops containing 0.3% drug provided noIOP-lowering effect compared to control. All other concentrations ofdrug reduced IOP in a dose-dependent manner. A plateau was reached at0.9% and there was no significant difference in drug response between0.9 and 1.2% drug (P>0.05). There was no significant difference betweenthe time of maximum response (T_(max)) values of 0.6-1.2% concentrationsof drug (P>0.05). In contrast, there was a significant differencebetween the time required for IOP to return to baseline (T_(end)) forall concentrations of pregabalin eye drops, (P<0.0001). The 1.2%pregabalin eye drops extended the duration of the IOP-lowering effect ofpregabalin above that obtained with 0.6% pregabalin. Because there wasno significant difference in the percent reduction of IOP between 0.9and 1.2% pregabalin, we selected 0.9% as the minimal concentrationrequired to produce the maximum reduction in IOP. Expanding thisanalysis to an additional species, we observed a similar IOP-loweringresponse (22.1±2.8%) in Dutch belted rabbits after instillation of 0.9%pregabalin eye drops (FIG. 5).

Extended Release Pregabalin Microemulsion formulation as a NovelGlaucoma Therapy

Primary open angle glaucoma (POAG) accounts for 90% of glaucoma casesworldwide. It is a leading cause for irreversible blindness. Elevatedintraocular pressure (IOP) is the most significant risk factor thatcontributes to visual field loss in POAG. IOP is generated by thebalance between the production and drainage of aqueous humor. Because ofthe importance of a tightly maintained IOP, its reduction is thefirst-line treatment for glaucoma. Despite glaucoma prevalence and itsimpact on society, current medications do not address the underlyingpathophysiologies that cause elevated IOP, nor do they address geneticvariations related to IOP modulation. Moreover, because of their shorthalf-life and low corneal residence time, they require multiple dailytopical applications, which are associated with poor patient compliance.We have developed novel extended release topical bioadhesivemicroemulsion (ME) formulations to deliver pregabalin (an exemplaryIOP-lowering drug) that will allow for once daily dosing and betterpatient compliance.

Formulation of Pregabalin-Loaded Bioadhesive Multilayered ME

Formulation of the bioadhesive multilayered ME hydrogel was achieved inthree steps. The first step included formation of the primarywater-in-oil (w/o) ME through construction of different triphasediagrams. The second step involved further emulsification of theproduced primary w/o ME into hydrophilic surfactant aqueous solution(i.e. surfactant with high value of hydrophilic lipophilic balance,HLB). The last step included the incorporation of the bioadhesivepolymer.

Construction of Triphase Diagrams and Preparation of the Primary w/o ME

The primary w/o ME usually consists of an oil phase, aqueous phase,single surfactant or surfactants mixture. To determine the appropriateratio of each component that can efficiently produce a ME, multipletriphase and pseudotriphase diagrams were constructed using Labrafaclipophile WL1349 as the oil phase, deionized water as the aqueous phaseand a single surfactant (in case of triphase diagram) or surfactantmixture (in case of pseudotriphase diagram) from the followingsurfactants: capryol 90; labrasol, cremophor EL; transcutol P; gelucire50/13; gelucire 44/14; geluccire 43/01; or soybean lecithin.

The triphase diagrams (FIG. 6-14) were generated using a water titrationmethod. In this method, oil was mixed with surfactant or surfactantsmixture in different ratios. The produced mixture was then titrated withdeionized water until the appearance of the first turbidity, whichreflects the boundary point that differentiates the end of the w/o MEregion and the beginning of the microemulsion region. In FIG. 16-14, thew/o ME region is shaded in black color and illustrate all the possiblecombinations of the three components that are capable of forming a ME.By selecting any point in that region, one can determine the percentageof the three components that can be easily mixed to form a w/o ME.

Preparation of the Multilayered w/o/w ME

Several triphase diagrams were constructed. The diagram represented inFIG. 12 was selected because it has the largest ME region. One point wasselected (though others would have worked as well) from this diagram tobe used for formulation of the multilayered water-in-oil-in-water(w/o/w) ME. All triphase diagrams were constructed using percent ratioof each ingredient (water, surfactant/surfactant mixture and oil) from0-100%. The selected w/o ME consisted of 20% water+30% oil (labrafaclipophile WL1349)+50% surfactant mixture (capryol 90 & soybean lecithin,1:1). The selection of this point was based on obtaining a stable w/oprimary emulsion with the highest possible amount of water in itsinternal phase that is capable of dissolving the drug in the requireddose. The selected concentration of the drug is 0.6%. To prepare thefinal multilayered w/o/w ME, several surfactants with high HLB werescreened to determine those that work well in the formulation of themultilayered w/o/w ME using titration method. The tested surfactantswere cremophor EL, labrasol, tween 80, poloxamer 188 and brij 97. Thesesurfactants may be used alone or in combination with each other or withother co-solvents such as polyethylene glycol, propylene glycol orglycerin. Aqueous solutions of different concentrations of thesesurfactants were prepared. The previously selected w/o was added dropwise to these solutions under continuous stirring until the appearanceof the first turbidity, which indicated the end of the ME formation andthe beginning of the macroemulsion formation. Among these surfactants,labrasol was not used at a concentration above 10% as it could result inirritation to the rabbits' eyes. Labrasol was used in combination withother surfactants (10% labrasol+10% cremophor EL+30% propylene glycol).By using this combination, the amount of w/o ME incorporated was 3.7 gm.The selected surfactant system is highlighted in Table 1.

TABLE 1 Different surfactant systems evaluated. Amount of w/o ME NumberSurfactant Concentration (gm)  1 Water — 0.01  2 tween 80 2.5% 0.02  3tween 80   5% 0.05  4 tween 80  10% 0.05  5 cremophor EL  10% 0.02  6poloxamer 188  10% 0.02  7 brij 97  10% 0.02  8 labrasol  10% 1  9labrasol  20% 1.6 10 labrasol  30% 2.5 11 labrasol  40% 3.2 12 propyleneglycol  40% 0.1 13 labrasol 20% + propylene glycol 10% 2 14 labrasol30% + propylene glycol 10% 4 15 labrasol 20% + propylene glycol 20% 3.2516 labrasol 10% + propylene glycol 30% 1.55 17 labrasol 10% + propyleneglycol 10% + tween-80 10% 1.2 18 labrasol 10% + propylene glycol 10% +brig-97 10% 1.2 19 labrasol 10% + propylene glycol 10% + cremophor-EL10% 1.65 20 labrasol 10% + propylene glycol 20% + cremophor-EL 10% 2.121 Labrasol 10% + propylene glycol 30% + cremophor EL 10% 3.7 22labrasol 5% + propylene glycol 30% + cremophor-EL 10% 2.5

Formulation of the Final Bioadhesive Multilayered ME Hydrogel

The external aqueous phase was prepared by dissolving 10% labrasol, 10%cremophor EL and 30% propylene glycol in distilled water. Thebioadhesive polymer (CARBOPOL® 981, sodium alginate or chitosan) wassoaked in the previously prepared surfactants solution and allowed toswell overnight. The previously prepared primary drug-loaded w/o isincorporated drop wise in this viscous polymer solution until gave thefinal clear multilayered w/o/w ME hydrogel (FIG. 15). Table 2 lists thechemical compositions of the three ME formulations we tested.

TABLE 2 Composition of pregabalin-loaded ME Chitosan Sod. alginateCARBOPOL ® Ingredient (% W/W) ME ME ME Pregabalin 0.6 0.6 0.6 Labrafaclipophile WL1349 7.8 7.8 7.8 Capryol 90 6.5 6.5 6.5 Lecithin 6.5 6.5 6.5labrasol 7.4 7.4 7.4 Cremophor EL 7.4 7.4 7.4 Propylene glycol 22.2 22.222.2 Chitosan 1.1 — — Sod. alginate — 0.4 — CARBOPOL ® 981 — — 0.15Deionized water to 100 100 100

Characterization of the Prepared Multilayered Pregabalin ME Hydrogels InVitro Characterizations

In vitro characterizations of the pregabalin ME hydrogel included: drugrelease study, cell toxicity study, viscosity determination,mucoadhesion study, and particle size and zeta potential determination.

Drug Release Study

The sustained release behaviors of pregabalin from differentformulations were studied in PBS (pH 7.4) using 1500 μl fastmicro-equilibrium dialyzer (Harvard Apparatus Co., Holliston. Mass.)with semipermeable regenerated cellulose membranes (Molecular weight cutoff 5,000 Da). The dialyzers were kept in a thermostatically controlledshaker at 35° C. and 50 rpm. Samples were withdrawn at predeterminedtime intervals for 24h and analyzed for their drug content by HPLC. Thetested formulations were CARBOPOL®, alginate, and chitosan MEs thatcontained 0.6% pregabalin in addition to 4 control formulationsincluding; CARBOPOL®, alginate, chitosan and water that contained 0.6%pregabalin. The release profiles (FIG. 16) show that all controlformulations exhibited fast release behaviors that released 100% of thedrug content within 3-8 h. On the other hand, the tested MEs exhibitedsustained release behaviors that last for up to 24 h.

Cell Toxicity Study

In-vitro cell toxicity of the ophthalmic formulations was tested usingan MTT assay method according to known protocols. Briefly, immortalizedhuman corneal limbal epithelial cell (HCLE) were seeded in 96-well plate(18,000 cell/well) with 200 μl growth medium and kept overnight at (37°C. & 5% CO₂) without disturbance to allow it to attach itself to thewell bottom. In the next day the medium was removed and replaced with200 μl of the formulation solution in the growth medium. Theformulations were kept in contact with the cells for 24h then replacedby 200 μl of (1 mg/ml) MTT solution. The plate was kept at (37° C. & 5%CO₂) for 4h to allow the cells to reduce MTT to the purple formazancrystals. After 4h, MTT solution was replaced by 200 μl DMSO to dissolvethe formazan crystals. The plate UV absorbance was measured at 570 nmusing microplate reader spectrophotometer. The cell viability for thetested formulations was calculated using their absorbance values as apercentage of the negative control (untreated cells) absorbanceaccording to the following equation;

${\% \mspace{14mu} {Cell}\mspace{14mu} {viability}} = {\frac{{Sample}\mspace{14mu} {absorbance}}{{Negative}\mspace{14mu} {control}\mspace{14mu} {absorbance}} \times 100}$

FIG. 17 shows at the formulations are safe and nontoxic or the corneaepithelial cells at the therapeutic dose. The experiment was repeated 8times for each formulation and the results were calculated as mean±SEM.

Viscosity Study

Viscosity of the formulations was measured using Brookfield cone andplate rotary viscometer according to a previously published protocol.Five hundred microliters of each formulation were placed between thecone and plate and allowed to equilibrate for 1 min to reach the runningtemperature. The measurements were done at 35° C.±0.5. The experimentwas repeated three times and the results were calculated as mean±SEM.FIG. 18 shows that the formulations containing CARBOPOL® possessed thehighest viscosity value, which allow them to remain inside the eye forlonger time. This improved corneal contact time will prolong the IOPlowering effect and help the sustained release of the drug.

Mucoadhesion Study

The formulations' mucoadhesion force was evaluated using an alreadypublished method. (Gallo EEHaJM 1990. A simple theological method forthe in vitro assessment of mucin-polymer bioadhesive bond strength.Pharmaceutical research 7(5):491-495; Mayol L, Quaglia F, BorzacchielloA, Ambrosio L, La Rotonda Mich. 2008. A novel poloxamers/hyaluronic acidin situ forming hydrogel for drug delivery: rheological, mucoadhesiveand in vitro release properties. Eur J Pharm Biopharm 70(1):199-206;Tayel S A, El-Nabarawi M A, Tadros M I, Abd-Elsalam W H 2013. Promisingion-sensitive in situ ocular nanoemulsion gels of terbinafinehydrochloride: design, in vitro characterization and in vivo estimationof the ocular irritation and drug pharmacokinetics in the aqueous humorof rabbits. Int J Pharm 443(1-2):293-305). Briefly, preheatedformulations (at 35° C.) were mixed with 15% dispersion of gastric mucin(at 35° C.) in 1:1 ratio. The viscosities of the formulations, mucin andtheir mixtures were measured using Brookfield cone and plate rotaryviscometer at 35° C. The change in the mixture viscosities weretranslated to bioadhesion force using the following equations:

η_(b) = η_(t) − (η_(m) + η_(r)) F = η_(b) · γ η_(b): change in viscosity(rheological η_(r): viscosity of the formulation (cP) synergism) (cP) F:mucoadhesion force (dyne/cm²) η_(t): viscosity of the mixture (cP) γ:shear rate (S⁻¹) η_(m): viscosity of mucin (cP)

The experiment was repeated three times and the results were calculatedas mean±SEM. FIG. 19 shows that the highest bioadhesion was present informulations that contained chitosan, which may be due to their positivecharge that increase their reaction with the negatively charged mucinand so improve their mucoadhesion.

Particle Size, Poly Dispersity Index (PDI) and Zeta PotentialDetermination

The particle size, PDI and zeta potential of the formulations weremeasured using zetasizer nano-ZS after suitable sample dilution (1:100for particle size and PDI and 1:1000 for zeta potential). The zetasizerdata of the MEs are listed in Table 3 as mean±SEM of at least 3readings. The particle size data show that all formulations possessed atiny particle size (<20 nm) with a very narrow particle sizedistribution. In an aspect of the invention, this tiny particle size isuseful for topical ophthalmic formulations since it does not cause agritty sensation that may bother the patient and affect his/hercompliance to use the medication and the tiny particle size can improvedrug penetration through the cornea by passive diffusion. The zetapotential charge differed according to the polymer used, which ispositive for chitosan and negative for both CARBOPOL® and alginate MEs.

TABLE 3 Particle size, PDI and zeta potential of different MEs. Particlesize (nm) PDI Zeta potential (mV) Formulation Blank Medciated BlankMedicated Blank Medicated Aliginate ME 16.8 ± 0.3 16.5 ± 0.2 0.34 ± 0.00.34 ± 0.0 −26.8 ± 0.8 −26.7 ± 1.7 Chitosan ME 17.4 ± 0.0 17.4 ± 0.30.36 ± 0.0 0.37 ± 0.0  15.9 ± 3.3  10.2 ± 2.3 CARBOPOL ^(®) ME 16.0 ±0.2 15.4 ± 0.1 0.26 ± 0.0 0.26 ± 0.0 −30.1 ± 2.2 −26.3 ± 1.0

Ex Vivo Characterization or Corneal Permeability Study

Modified Franz diffusion cells were used for corneal drug permeabilitystudies for different formulations. The modified Franz diffusion cellconsists of two vertically connected chambers (donor and receptorchambers) attached to each other through a spherical junction that issuitable for spherical tissues (i.e. cornea). The volume of the donorchamber was 0.5 ml and that of the receptor chamber was 5 ml. Thereceptor chamber was stirred at 50 rpm by the aid of a magnetic stir barto allow continuous mixing of the chamber contents. The orifice at thejunction between the two chambers has a 9 mm diameter at which thecorneal tissue was fixed and the drug allowed to diffuse. One hundredmicroliters of each formulation was placed in the donor chamber. Thereceptor chamber was filled by 5 ml of BSS-Plus (balanced saltsolution-plus) and the whole cell was surrounded by a warm water jacketto maintain the temperature at 35° C. A sample of 0.5m was withdrawnfrom the receptor chamber every 1 h for a total period of 6h andreplaced by a fresh BSS-Plus that maintained at 35° C. The collectedsamples were assayed for their drug contents using a standard HPLCprotocol. The experiment was repeated six times and the results werecalculated as mean±SEM. The cumulative amount that permeated through thecornea for six hours for each formulation was plotted and the data shownin FIG. 20. Pregabalin is a BCS class-I drug, which means that it is ahighly permeable and highly soluble drug. FIG. and Table 4 show that theME-free formulation (Preg/water and Preg/CARBOPOL®) possessed a higherpermeation rate than the formulation containing ME. This is because ofthe natural ability of the drug to rapidly permeate through the cornea,which when given on its own, does not allow for a sustained release ofthe drug over time. All formulations containing ME possessed a lowerpermeation rate than Pregabalin alone. By using any formulationscontaining ME and the drug, sustained release is possible. Uponcomparing the ME formulations, it was found that the formulation thatcontained CARBOPOL® possessed the lowest permeation rate among alltested formulations. This experiment confirmed the in vitro release datathat an ME can sustain pregabalin release for once daily application.

TABLE 4 In vitro transcorneal permeability parameters of pregabalin MEand control Rate of Permeability permeation Flux coefficient Formulation(dM/dt) (μg/cm²/min) (P) x10⁻⁴ PRG in water 0.285 ± 0.1 0.45 ± 0.13 7.5± 2.2 PRG in CARBOPOL ® 0.374 ± 0.15 0.59 ± 0.24 9.8 ± 3.9 PRG chitosanME 0.233 ± 0.06 0.37 ± 0.10 6.1 ± 1.7 PRG sod. alginate ME 0.287 ± 0.180.45 ± 0.28 7.5 ± 4.7 PRG CARBOPOL ® ME 0.288 ± 0.08 0.45 ± 0.13 7.6 ±2.2

In Vitro Characterization or IOP-Lowering Study on Dutch Belted RabbitsFormulation Safety

The safety of ME formulations was tested by installation of 100 μl ofeach formulation in the lower conjunctival sac of the right eye of DutchBelted rabbits (n=3) while the left eye served as a control. Eyes wereexamined every hour for any sign of irritation such as redness, tearing,conjunctival swelling or corneal swelling. Slit-lamp examination wasperformed for all rabbit eyes at the end at the experiment. FIG. 21 areexemplary photographs of slit-lamp examination after the application ofthe ME formulations. The figure shows that no signs of irritation weredetected: the cornea was clear and there was no swelling, the lens wasclear, and the aqueous humor was clear with no cells or flare.

Formulation Efficacy

The IOP-lowering effect of the formulations was determined using asingle dose-response design. Dutch Belted (DB) rabbits (n=3) were usedfor this study, during which each rabbit received 100 μl of themedicated formulation in the lower conjunctival sac of its right eyewhile the left eye served as a control by receiving 100 μl of the blankformulation. The intraocular pressure (IOP) was measured using Tonopen(Tono-pen AVIA Vet, Reichert) immediately before the application of theformulation (baseline) and at predetermined time intervals until itreturned back to its baseline value.

FIG. 22 shows the IOP profile of DB rabbits after application of theCARBOPOL® ME formulation containing different concentrations ofpregabalin (0.1-0.7%). There was a dose dependent increase in theIOP-lowering efficacy of the formulations until 0.6%. There was nosignificant difference between 0.6% and 0.7% pregabalin. Therefore 0.6%pregabalin was selected as the minimum dose that gave the maximumresponse.

To identify the formulation that provided the maximum IOP-loweringefficacy, we performed a single dose-response design study using DutchBelted rabbits by varying the external aqueous phase of the ME. Table 5lists the calculated pharmacodynamic parameters based on the IOPprofiles and Table 6 provides the statistical comparisons. Based on theresults, the CARBOPOL® ME provides good IOP-reduction and extendedeffect.

TABLE 5 Pharmacodynamic parameters after application of 0.6% pregabalinin different ME of different formulations to Dutch belted rabbits.Ophthalmic formulations PD parameters Preg in (mean ± SEM) Carb ME Sodalg ME Chitosan ME Carb Baseline IOP  21.4 ± 0.7 20.9 ± 0.2 21.2 ± 0.422.1 ± 0.4 (mmHg) I_(max) (mmHg)  13.1 ± 0.7 13.7 ± 0.4 14.2 ± 1.2 16.2± 0.4 IOP reduction  −8.3 ± 0.2 −7.2 ± 0.5 −7.0 ± 1.5 −5.9 ± 0.8 (mmHg)% IOP Reduction  38.7 ± 1.3 34.4 ± 2.2 32.8 ± 6.6 26.6 ± 3.1 T_(max) (h) 3.3 ± 0.9  3.7 ± 0.3  4.0 ± 1.0  3.3 ± 1.4 T_(end) (h)  32.7 ± 1.3 24.0± 0.0 20.0 ± 0.0 10.0 ± 0.0 AUC (mmHg · h) 169.9 ± 13.4 80.7 ± 4.6 69.5± 14.2 39.0 ± 4.0

TABLE 6 Statistical comparisons among different pregabalin ME eye dropsand the control after application of a single dose Sod. alg Sod. algPharmacodynamic Overall Carb ME vs Carb ME vs Carb ME vs ME vs ME vsChitosan vs Parameters P value Sod. Alg ME Chitosan ME Preg in CarbChitosan ME Preg in Carb PRg in Carb % Reduction in IOP0.2504 >0.05 >0.05 >0.05 >0.05 >0.05 >0.05 T_(max) (h)0.9567 >0.05 >0.05 >0.05 >0.05 >0.05 >0.05 T_(end) (h) <0.0001 <0.001<0.0001 <0.0001 <0.05 <0.0001 <0.0001 AUC_(total) (% h) 0.0001 <0.01<0.001 <0.0001 >0.05 >0.05 >0.05FIG. 23 shows a comparison between both CARBOPOL® formulations (gel andME) which demonstrates that the ME greatly extends the duration of thedrug effect. Evaluation of the formulation was achieved by comparingbetween their pharmacodynamics (PD) parameters, which includedpercentage of the maximum reduction in IOP (% I_(max)), time at whichmaximum IOP reduction occurs (T_(max)), time required for IOP to returnback to its baseline value (T_(end)) and the area under the IOP-timecurve (AUC).

Tachyphylaxis Study of Pregabalin CARBOPOL® ME

To determine if the pregabalin CARBOPOL® ME was able to maintain IOP ata reduced level after multiple dosings, we performed a tachyphylaxisstudy for 21 days. A single drop of pregabalin loaded ME formulation wasinstilled into the right eye of Dutch belted rabbits and blank ME wasinstilled into the left eye at Sam each day for 3 weeks. IOP wasmeasured every 1-2 hours on days 1 and 21, while on all other days itwas measured twice per day. FIG. 24 demonstrates that the IOP of themedicated eye was reduced by 30.7% at the T_(max) of day 1. IOP startedto return toward baseline IOP but was still reduced by 20.5% by 24 hoursafter receiving the first dose (FIG. 25). After receiving the 2^(nd)dose of ME formulation, IOP was maintained in a normal physiologicalrange between 12 and 13 mmHg throughout the duration of the study (FIGS.24 and 26).

Efficacy of Other Gabapentinoid Drugs

To determine if other members of the gabapentinoid drug family are alsoefficacious in reducing IOP, we compared the efficacy of 0.9%pregabalin, 0.9% 2-phenylglycine and 0.9% gabapentin in 2% HPMC viscouseye drops in C57Bl/6J mice.

Pregabalin in viscous eye drops gave a maximum IOP reduction of 17.3%that returned to baseline by 6 hrs with an area under the curve of 65%hr (FIG. 27). 2-phenylglycine (FIG. 28) and gabapentin (FIG. 29) werenot as efficacious as pregabalin although they both had maximum IOPreductions of 8% and areas under the curve of 14% hr. These datademonstrate that although they are not as effective in reducing IOP,both 2-phenylglycine and gabapentin are able to induce an IOP-loweringresponse.

Pregabalin CARBOPOL® ME Non-Inferiority Test

To determine how our pregabalin ME formulation compared to a marketleader IOP-lowering drug, we evaluated Lumigan 0.01% in our same Dutchbelted rabbit formulation. In humans, Lumigan is dosed at night beforebed. We evaluated dosing at 9 am and 9 pm. In rabbits dosed both at 9 am(FIG. 30) and 9 pm (FIG. 31), there was no difference in IOP betweentreated with Lumigan or vehicle. The time of dosing did not affect thelack of IOP lowering response.

Therefore, our pregabalin ME is not inferior to the market leaderIOP-lowering drops.Evaluation of ME Compatibility with Other Water Soluble Drugs

To determine if our pregabalin CARBOPOL® ME is compatible with otherwater-soluble drugs, we synthesized and characterized a ribavirin-loadedCARBOPOL® ME using identical methods. Ribavirin is an antiviralmedication used to treat respiratory syncytial virus infection,hepatitis C, and viral hemorrhagic fever. It can also be used to treatviral infections of the eye such as Herpes simplex keratitis, a diseaseof the corneal epithelium. Ribavirin is a synthetic nucleoside analogue.Its chemical name is1-β-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide, its empiricalformula is C₈H₁₂N₄O₅ and the molecular weight is 244.21. Ribavirin is awhite, crystalline powder. It is freely soluble in water, likepregabalin.

Drug Release Study of Ribavirin

The sustained release behavior of ribavirin from different formulationswas studied using identical methods detailed above for pregabalin. Therelease profiles (FIG. 32) demonstrate that all control formulationsexhibited fast release behaviors that released 100% of the drug contentwithin 3-4 h. In contrast, the tested MEs exhibited sustained releasebehaviors that lasts for up to 24 h.

Cell Toxicity Study of Ribavirin ME Formulations

I-vitro cell toxicity of the formulations was tested by MTT assay methodusing identical methods detailed above for pregabalin. FIG. 33 showsthat the formulations are safe and nontoxic for the corneal epithelialcells at the therapeutic dose. The experiment was repeated 8 times foreach formulation and the results were calculated as mean±SEM.

Viscosity Study of Ribavirin ME Formulations

Viscosity of the formulations was measured using identical methodsdetailed above for pregabalin. FIG. 34 shows that the formulationscontaining CARBOPOL® possessed the highest viscosity, which allows themto remain inside the eye for longer time.

Mucoadhesion Study of Ribavirin ME Formulations

The formulations mucoadhesion force was evaluated using identicalmethods detailed above for pregabalin. The experiment was repeated threetimes and the results were calculated as mean±SEM. FIG. 35 shows thatthe highest bioadhesion was present in formulations that containedCARBOPOL®.

Particle Size, Poly Dispersity Index (PDI) and Zeta PotentialDetermination of Ribavirin ME Formulations

The particle size, PDI and zeta potential of the formulations ofRibavirin formulations were measured using identical methods detailedabove for pregabalin. The zetasizer data of the MEs are listed in Table7 as mean±SEM of at least 3 readings. The particle size data show thatall formulations possessed a tiny particle size (<20 nm) with a verynarrow particle size distribution.

TABLE 7 Particle size, PDI and zeta potential of Ribavirin containingMEs Particle size (nm) PDI Zeta potential (mV) Formulation BlankMedicated Blank Medicated Blank Medicated Aliginate ME 10.8 ± 0.3 10.7 ±0.04 0.304 ± 0.0 0.303 ± 0.0 −19.1 ± 0.96 −20.4 ± 1.9 CARBOPOL ME  9.2 ±0.1  9.1 ± 0.04 0.155 ± 0.0 0.163 ± 0.0 −23.7 ± 1.1  −21.4 ± 1.8

Ex Vitro Characterization or Corneal Permeability Study of Ribavirin MEFormulations

Ribavirin containing formulations were characterized using identicalmethods detailed above for pregabalin. The cumulative amount permeatedthrough cornea for six hours for each formulation was plotted and thedata shown in FIG. 36 and Table 8. Ribavirin is a BCS class-III drug,which means that it is a not highly permeable, yet it is highly solubledrug. FIG. 36 shows that the ME formulations increased the permeationrate over Ribavirin alone.

TABLE 8 In vitro transcorneal permeability parameters of pregabalin MEand control Rate of Permeability permeation Flux coefficient Formulation(dM/dt) (μg/cm²/min) (P) x10⁻⁴ PRG in water 0.285 ± 0.1 0.45 ± 0.13 7.5± 2.2 PRG in CARBOPOL ® 0.374 ± 0.15 0.59 ± 0.24 9.8 ± 3.9 PRG chitosanME 0.233 ± 0.06 0.37 ± 0.10 6.1 ± 1.7 PRG sod. alginate ME 0.287 ± 0.180.45 ± 0.28 7.5 ± 4.7 PRG CARBOPOL ® ME 0.288 ± 0.08 0.45 ± 0.13 7.6 ±2.2

In closing, it is to be understood that although aspects of the presentspecification are highlighted by referring to specific embodiments, oneskilled in the art will readily appreciate that these disclosedembodiments are only illustrative of the principles of the subjectmatter disclosed herein. Therefore, it should be understood that thedisclosed subject matter is in no way limited to a particularmethodology, protocol, and/or reagent, etc., described herein. As such,various modifications or changes to or alternative configurations of thedisclosed subject matter can be made in accordance with the teachingsherein without departing from the spirit of the present specification.Lastly, the terminology used herein is for the purpose of describingparticular embodiments only and is not intended to limit the scope ofthe present invention, which is defined solely by the claims.Accordingly, the present invention is not limited to that precisely asshown and described.

Certain embodiments of the present invention are described herein,including the best mode known to the inventors for carrying out theinvention, Of course, variations on these described embodiments willbecome apparent to those of ordinary skill in the art upon reading theforegoing description. The inventor expects skilled artisans to employsuch variations as appropriate, and the inventors intend for the presentinvention to be practiced otherwise than specifically described herein.Accordingly, this invention includes all modifications and equivalentsof the subject matter recited in the claims appended hereto as permittedby applicable law. Moreover, any combination of the above-describedembodiments in all possible variations thereof is encompassed by theinvention unless otherwise indicated herein or otherwise clearlycontradicted by context.

Groupings of alternative embodiments, elements, or steps of the presentinvention are not to be construed as limitations. Each group member maybe referred to and claimed individually or in any combination with othergroup members disclosed herein. It is anticipated that one or moremembers of a group may be included in, or deleted from, a group forreasons of convenience and/or patentability. When any such inclusion ordeletion occurs, the specification is deemed to contain the group asmodified thus fulfilling the written description of all Markush groupsused in the appended claims.

Unless otherwise indicated, all numbers expressing a characteristic,item, quantity, parameter, property, term, and so forth used in thepresent specification and claims are to be understood as being modifiedin all instances by the term “about.” Accordingly, unless indicated tothe contrary, the numerical parameters set forth in the specificationand attached claims are approximations that may vary. At the very least,and not as an attempt to limit the application of the doctrine ofequivalents to the scope of the claims, each numerical indication shouldat least be construed in light of the number of reported significantdigits and by applying ordinary rounding techniques. Notwithstandingthat the numerical ranges and values setting forth the broad scope ofthe invention are approximations, the numerical ranges and values setforth in the specific examples are reported as precisely as possible.Any numerical range or value, however, inherently contains certainerrors necessarily resulting from the standard deviation found in theirrespective testing measurements. Recitation of numerical ranges ofvalues herein is merely intended to serve as a shorthand method ofreferring individually to each separate numerical value falling withinthe range. Unless otherwise indicated herein, each individual value of anumerical range is incorporated into the present specification as if itwere individually recited herein,

The terms “a,” “an,” “the” and similar referents used in the context ofdescribing the present invention (especially in the context of thefollowing claims) are to be construed to cover both the singular and theplural, unless otherwise indicated herein or clearly contradicted bycontext. All methods described herein can be performed in any suitableorder unless otherwise indicated herein or otherwise clearlycontradicted by context. The use of any and all examples, or exemplarylanguage (e.g., “such as”) provided herein is intended merely to betterilluminate the present invention and does not pose a limitation on thescope of the invention otherwise claimed. No language in the presentspecification should be construed as indicating any non-claimed elementessential to the practice of the invention.

Specific embodiments disclosed herein may be further limited in theclaims using consisting of or consisting essentially of language. Whenused in the claims, whether as filed or added per amendment, thetransition term “consisting of” excludes any element, step, oringredient not specified in the claims. The transition term “consistingessentially of” limits the scope of a claim to the specified materialsor steps and those that do not materially affect the basic and novelcharacteristic(s). Embodiments of the present invention so claimed areinherently or expressly described and enabled herein.

All patents, patent publications, and other publications referenced andidentified in the present specification are individually and expresslyincorporated herein by reference in their entirety for the purpose ofdescribing and disclosing, for example, the compositions andmethodologies described in such publications that might be used inconnection with the present invention. These publications are providedsolely for their disclosure prior to the filing date of the presentapplication. Nothing in this regard should be construed as an admissionthat the inventors are not entitled to antedate such disclosure byvirtue of prior invention or for any other reason. All statements as tothe date or representation as to the contents of these documents isbased on the information available to the applicants and does notconstitute any admission as to the correctness of the dates or contentsof these documents.

We claim:
 1. A microemulsion (ME), comprising: (a) a discontinuousinternal phase comprising an aqueous solution encompassed within aninternal emulsifier; (b) a continuous oil phase encompassing theinternal phase; and (c) an external emulsifier encompassing the oilphase.
 2. The ME of claim 1, further comprising (d) an aqueous phasesurrounding the external emulsifier.
 3. The ME of claim 1 or 2, whereinthe internal emulsifier is selected from the group consisting ofpropylene glycol monocaprylate or any other surfactant with an HLB value3-7 and/or propylene glycol ester of any fatty acid such as; propyleneglycol monocaproate, propylene glycol monocaprylate, propylene glycolmonocaprate, propylene glycol monolaurate, propylene glycolmonostearate, propylene glycol monopalmitate, polyethylene glycol laurylether, polyethylene glycol oleyl ether, polyethylene glycol hexadecylether, sorbitan monopalmitate, sorbitan monostearate, sorbitanmonooleate, sorbitan monolaurate, transcutol P, gelucire 50/13, gelucire44/14, gelucire 43/01, any PEG mono-, di- and/or tri-esters of any fattyacid, lecithin, egg lecithin, phosphatidylcholine,phosphatidylethanolamine, phosphatidylinositol, tocopherol or any otherphospholipid, and combinations thereof.
 4. The ME of claim 1 or 2,wherein the internal emulsifier is selected from the group consisting ofcaproyl 90, lecithin, and combinations thereof.
 5. The ME of any one ofclaims 1-4, wherein the aqueous solution is selected from the groupconsisting of deionized water, saline, phosphate buffered saline,artificial tears, balanced salt solution.
 6. The ME of any one of claims1-5, wherein the oil phase is selected from the group consisting of anoil that consists of medium chain triglycerides of caprylic (C₈) andcapric (C₁₀) acids, any pure fatty acid ester including but not limitedto ethyl, propyl isopropyl, and butyl; esters of fatty acids includingbut not limited to caproic, caprylic, capric, lauric, palmitic,myristic, or stearic acids, isopropyl myristate, isopropyl palmitate,isopropyl caproate, isopropyl caprylate, ethyl stearate, butyl laurate,and any natural oil including but not limited to coconut oil, palmkernel oil, soya bean oil castor oil, cotton seed oil, corn oil, andolive oil; and combinations thereof.
 7. The ME of any one of claims 1-5,wherein the oil phase comprises labrafac lipophile WL
 1349. 8. The ME ofany one of claims 1-7, wherein the external emulsifier is selected fromthe group consisting of caprylocaproyl polyoxyl-8 glycerides,macrogolglycerol ricinoleate, any other hydrophilic surfactant withHydrophile-Lipophile Balance (HLB) value between 10-16, polyethyleneglycol mono- and/or di-esters of any fatty acid or fatty acid mixture,propylene glycol or any other alcohol including but not limited toglycerol, polyethylene glycol, ethanol, propanol, and isopropanol; andcombinations thereof.
 9. The ME of any one of claims 1-8, wherein theexternal emulsifier comprises caprylocaproyl polyoxyl-8 glycerides,macrogolglycerol ricinoleate, propylene glycol, or combinations thereof.10. The ME of any one of claims 1-9, wherein the ME contains 0.5-35% w/waqueous solution, 0.5-95% w/w oil phase, and 5-99% w/w emulsifier. 11.The ME of any one of claims 1-9, wherein the ME contains 10-30% w/waqueous solution, 20-40% w/w oil phase, and 40-60% w/w emulsifier. 12.The ME of any one of claims 1-11, wherein the aqueous solution comprisesa water soluble drug.
 13. The ME of claim 12, wherein the water solubledrug is selected from the group consisting of beta-blockers such asbetaxolol and timolol; prostaglandin analogs such as bimatoprost,latanoprost, and travoprost; Alpha-adrenergic agents such as brimonidinetartrate; carbonic anhydrase inhibitors such as brinzolamide,dorzolamide, and acetazolamide; calcium channel blockers such asnimodipine and pregabalin; asialo, galactosylated, triantennary(NA3)(also known as asialo-, tri-antennary complex-type N-glycan),OT-551 hydrochloride (1-hydroxy-2,2,6,6-tetramethyl-4-piperidinylcyclopropane carboxylic acid ester hydrochloride), brimonidine tartrate,clindamycin, ciprofloxacin, levofloxacin, gatifloxacin, gemifloxacin,ofloxacin, triamcinolone, valacyclovir, pyrimethamine, valganciclovir,ganciclovir, acyclovir, foscarnet, prednisolone acetate, dilupednate,triamcinolone, dexamethasone, methotrexate, azathioprine, mycophenolatemofetil, cyclosporine, tacrolimus, cyclophosphamide, ribavirin,bromfenac, ketorolac, nepafenac, lifitegrast, flubiprofen, diclonfenac,ketotifen, nedocromil, phenylephrine, azelastine, epinastine,naphazolincipheniramine, oloptadine, bepotastine, alacafnadine,pemirolast, tetrahydrozoline with or without zinc sulfate, lodoxamide,naphazoline, phenylephrine, cromolyn, emedastine, oxymetazoline,xylometazoline, loratidine, desloratidine, phenylglycine, gabapentin,combinations thereof, or pharmaceutically acceptable salts thereof. 14.The ME of claim 12, wherein the water soluble drug is selected from thegroup consisting of phenylglycine, gabapentin, pregabalin and ribavirin,or a pharmaceutically acceptable salt thereof.
 15. The ME of any one ofclaims 1-14, wherein the aqueous phase comprises a hydrogel
 16. The MEof claim 15, wherein the hydrogel comprises mucoadhesive polymers. 17.The ME of claim 16, wherein the mucoadhesive polymers are selected fromthe group consisting of polyacrylic acid derivatives (including but notlimited to CARBOPOL®, such as CARBOPOL® 981), alginic acid and its saltsor derivatives (including but not limited to sodium alginate), chitosanand its derivatives, dextran and its derivatives, pectin and itsderivatives, gelatin and its derivatives, polyvinylpyrrolidone and itsderivatives, N-methylpyrrolidone and its derivatives, hyaluronic acidsalts and derivatives thereof, gellan gum and derivatives thereof,xanthan gum and derivatives thereof, agar and derivatives thereof,glycocholic acid and its salts or derivatives, or combinations thereof.18. The ME of claim 16, wherein the mucoadhesive polymers are selectedfrom the group consisting of polyacrylic acid derivatives (including butnot limited to CARBOPOL®, such as CARBOPOL® 981), alginic acid and itssalts or derivatives (including but not limited to sodium alginate),chitosan and its derivatives, or combinations thereof.
 19. The ME of anyone of claims 1-18, wherein the ME is present as globules between about1 am and about 200 nm in diameter.
 20. The ME of any one of claims 1-19,wherein the ME is formulated as a topical formulation.
 21. A method fortreating an eye disease, comprising administering to a subject with aneye disease an amount effective to treat the eye disease of the ME ofany one of claims 1-20, wherein the aqueous solution comprises a watersoluble drug capable of treating the eye disease.
 22. A method forreducing intraocular pressure (IOP), treating glaucoma, treatingage-related macular degeneration (AMD), treating uveitis, and/ortreating conjunctivitis, comprising administering to a subject withintraocular pressure, glaucoma, AMD, uveitis, and/or conjunctivitis anamount effective to reduce intraocular pressure, treat glaucoma, treatAMD, treat uveitis, and/or treat conjunctivitis of the ME of any one ofclaims 1-20, wherein the aqueous solution comprises a water soluble drugcapable of reducing IOP, treating glaucoma, treating AMD, treatinguveitis, and/or treating conjunctivitis.
 23. The method of claim 21 or22, wherein the water soluble drug capable of reducing IOP, treatingglaucoma, treating AMD, treating uveitis, and/or treating conjunctivitisis selected from the group consisting of beta-blockers such as betaxololand timolol; prostaglandin analogs such as bimatoprost, latanoprost, andtravoprost; Alpha-adrenergic agents such as brimonidine tartrate;carbonic anhydrase inhibitors such as brinzolamide, dorzolamide, andacetazolamide; calcium channel blockers such as nimodipine andpregabalin; asialo, galactosylated, triantennary (NA3) (also known asasialo-, tri-antennary complex-type N-glycan), OT-551 hydrochloride(1-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl cyclopropane carboxylicacid ester hydrochloride), brimonidine tartrate, clindamycin,ciprofloxacin, levofloxacin, gatifloxacin, gemifloxacin, ofloxacin,triamcinolone, valacyclovir, pyrimethamine, valganciclovir, ganciclovir,acyclovir, foscarnet, prednisolone acetate, diflupednate, triamcinolone,dexamethasone, methotrexate, azathioprine, mycophenolate mofetil,cyclosporine, tacrolimus, cyclophosphamide, ribavirin, bromfenac,ketorolac, nepafenac, lifitegrast, flubiprofen, diclonfenac, ketotifen,nedocromil, phenylephrine, azelastine, epinastine,naphazoline/pheniramine, oloptadine, bepotastine, alacafladine,pemirolast, tetrahydrozoline with or without zinc sulfate, lodoxamide,naphazoline, phenylephrine, cromolyn, emedastine, oxymetazoline,xylometazoline, loratidine, desloratidine, phenylglycine, gabapentin,combinations thereof, or pharmaceutically acceptable salts thereof. 24.The method of claim 21 or 22, wherein the water soluble drug capable ofreducing IOP, treating glaucoma, treating AMD, treating uveitis, and/ortreating conjunctivitis is selected from the group consisting ofphenylglycine, gabapentin, pregabalin and ribavirin, or pharmaceuticallyacceptable salts thereof.
 25. The method of any one of claims 21-24,wherein the ME is administered to one or both eyes of the subject. 26.The method of any one of claims 21-24, wherein the administering is doneonce per day.
 27. A microemulsion (ME) comprising: (a) a discontinuous(dispersed) oil phase; and (b) an emulsifier encompassing the oil phase.28. The ME of claim 27, further comprising (c) a continuous aqueousphase surrounding the emulsifier.
 29. The ME of claim 27 or 28, furthercomprising an insoluble or sparingly soluble drug in the discontinuousoil phase.
 30. A method for treating glaucoma, comprising administeringto a subject with glaucoma an amount effective to treat glaucoma of aninhibitor of Calcium Voltage-Gated Channel Auxiliary Subunit Alpha2delta1 (CACNA2d1) protein.
 31. The method of claim 29, wherein the glaucomais primary open angle glaucoma (POAG).
 32. A method for reducingintraocular pressure, comprising administering to a subject in needthereof an amount effective to treat reduce intraocular pressure of aninhibitor of CACNA2d1 protein.
 33. The method of any one of claims30-32, wherein the inhibitor comprises a gabapentanoid, phenylglycine,or a pharmaceutically acceptable salt thereof.
 34. The method of claim33, wherein the gabapentanoid comprises gabapentin, pregabalin, or apharmaceutically acceptable salt thereof.
 35. The method of any one ofclaims 30-34, wherein the inhibitor is administered topically.
 36. Themethod of any one of claims 30-35, wherein the inhibitor is administeredvia eye drops.
 37. A formulation, wherein the formulation comprises: (a)a primary water-in-oil (w/o) phase constituting between about 0.1% andabout 40% of the formulation, wherein the w/o phase comprises: (i) waterat a concentration of between 0% and about 7% w/w of the formulation;(ii) oil at a concentration of between about 6% and about 13% w/w of theformulation; (iii) capryol 90 at a concentration of between about 1% andabout 13% w/w of the formulation; and (iv) lecithin at a concentrationof between about 1% and about 13% w/w of the formulation; and (b) anexternal aqueous phase constituting 50-99.9% of the formulation, whereinthe external aqueous phase comprises: (i) labrasol at a concentration ofbetween about 0.1% and about 25% w/w of the formulation; (ii) cremophorEL at a concentration of between about 0.1% and about 25% w/w of theformulation; (iii) propylene glycol at a concentration of between 0% andabout 45% w/w of the formulation; and (iv) water at a concentration ofbetween about 10/and about 99.7% w/w of the formulation.
 38. Aformulation, wherein the formulation comprises: (a) a primarywater-in-oil (w/o) phase constituting between about 0.1% and about 40%of the formulation, wherein the w/o phase comprises: (i) water at aconcentration of between 2% and about 7% w/w of the formulation; (ii)oil at a concentration of between about 6% and about 9% w/w of theformulation; (iii) Capryol 90 at a concentration of between about 3% andabout 9% w/w of the formulation; and (iv) lecithin at a concentration ofbetween about 3% and about 9% w/w of the formulation; and (b) anexternal aqueous phase constituting 50-99.9% of the formulation, whereinthe external aqueous phase comprises: (i) labrasol at a concentration ofbetween about 5% and about 9.5% w/w of the formulation; (ii) CremophorEL at a concentration of between about 5% and about 9.5% w/w of theformulation; (iii) propylene glycol at a concentration of between 5% andabout 25% w/w of the formulation; and (iv) water at a concentration ofbetween about 30% and about 56% w/w of the formulation.
 39. A method oftreating a disease of the eye, wherein a subject is administered theformulation of claim 37 or
 38. 40. The method of claim 39, wherein thedisease of the eye is IOP, glaucoma, AMD, uveitis, and/orconjunctivitis.
 41. The method of any one of claims 39-40, wherein theformulation is administered to the eye of a patient.
 42. The method ofany one of claims 39-41, wherein the formulation is administered to thepatient once a day.
 43. The method of any one of claims 39-41, whereinthe formulation is administered to the patient two or more times a day.44. The method of any one of claims 21-26, 30-36, or 40-43, wherein theformulation results in a reduction of (OP, glaucoma, AMD, uveitis,and/or conjunctivitis by at least 10%, at least 15%, at least 20%, atleast 25%, at least 30%, at least 35%, at least 40%, at least 45%, atleast 50%, at least 55%, at least 60%, at least 65%, at least 70%, atleast 75%, at least 80%, at least 85%, at least 90% or at least 95%. 45.The method of any one of claims 21-26, 30-36, or 40-43, wherein theformulation results in a reduction of IOP, glaucoma, AMD, uveitis,and/or conjunctivitis from about 5% to about 100%, about 10% to about100%, about 20% to about 100%, about 30% to about 100%, about 40% toabout 100%, about 50% to about 100%, about 60% to about 100%, about 70%to about 100%, about 80% to about 100%, about 10% to about 90%, about20% to about 90%, about 30% to about 90%, about 40% to about 90%, about50% to about 90%, about 60% to about 90%, about 70% to about 90%, about10% to about 80%, about 20% to about 80%, about 30% to about 80%, about40% to about 80% about 50% to about 80%, or about 60% to about 80%,about 10% to about 70%, about 20% to about 70%, about 30% to about 70%,about 40% to about 70%, or about 50% to about 70%.
 46. The method of anyone of claims 39-45, wherein the formulation includes a water-solubledrug.
 47. The method of claim 46, wherein the formulation includes oneor more of pregabalin, phenylglycine, gabapentin, or ribavirin.
 48. Themethod of claim 46, wherein the formulation includes pregabalin.
 49. Themethod of any one of claims 21-26, 30-36, or 39-48, wherein the ME orformulation includes at least 0.3% w/w, at least 0.4% w/w, 0.5% w/w, atleast 0.6% w/w, at least 0.7% w/w, at least 0.8% w/w, at least 0.9% w/w,at least 1.0% w/w, at least 1.1% w/w, at least 1.2% w/w of awater-soluble drug.
 50. The method of any one of claims 21-26, 30-36, or39-48, wherein the ME or formulation includes about 0.3% w/w to about1.2% w/w, about 0.3% w/w to about 1.1% w/w, about 0.3% w/w to about 1.0%w/w, about 0.3% w/w to about 0.9% w/w, about 0.3% w/w to about 0.8% w/w,about 0.4% w/w to about 1% w/w, about 0.4% w/w to about 0.9% w/w, about0.4% w/w to about 0.8% w/w, about 0.4% w/w to about 0.7% w/w, about 0.5%w/w to about 1.0% w/w, about 0.5% w/w to about 0.9% w/w, about 0.5% w/wto about 0.8% w/w, about 0.5% w/w to about 0.7% w/w, about 0.55% w/w toabout 0.8% w/w, or about 0.55% w/w to about 0.7% w/w of a water-solubledrug.
 51. The method of any one of claims 21-26, 30-36, or 46-50,wherein the concentration of the water-soluble drug is at least 0.3%w/w, at least 0.4% w/w, 0.5% w/w, at least 0.6% w/w, at least 0.7% w/w,at least 0.8% w/w, at least 0.9% w/w, at least 1.0% w/w, at least 1.1%w/w, at least 1.2% w/w of the ME or formulation.
 52. The method of anyone of claims 21-26, 30-36, or 46-50, wherein the concentration of thewater-soluble drug is at most 0.3% w/w, at most 0.4% w/w, at most 0.5%w/w, at most 0.6% w/w, at most 0.7% w/w, at most 0.8% w/w, at most 0.9%w/w, at most 1.0% w/w, at most 1.1% w/w, or at most 1.2% w/w of thefinal ME or formulation.
 53. The method of any one of claims 21-26,30-36, or 46-50, wherein the concentration of the water-soluble drug isabout 0.3% w/w to about 1.2% w/w, about 0.3% w/w to about 1.1% w/w,about 0.3% w/w to about 1.0% w/w, about 0.3% w/w to about 0.9% w/w,about 0.3% w/w to about 0.8% w/w, about 0.4% w/w to about 1% w/w, about0.4% w/w to about 0.9% w/w, about 0.4% w/w to about 0.8% w/w, about 0.4%w/w to about 0.7% w/w, about 0.5% w/w to about 1.0% w/w, about 0.5% w/wto about 0.9% w/w, about 0.5% w/w to about 0.8% w/w, about 0.5% w/w toabout 0.7% w/w, about 0.55% w/w to about 0.8% w/w, or about 0.55% w/w toabout 0.7% w/w of the ME or formulation.
 54. The method of any one ofclaims 21-26, 30-36, or 39-53, wherein the ME or formulation includes awater-soluble drug that reduces a symptom of IOP, glaucoma, AMD,uveitis, and/or conjunctivitis, by at least 20%, at least 25%, at least30%, at least 35%, at least 40%, at least 45%, at least 50%, at least55%, at least 60%, at least 65%, at least 70%, at least 75%, at least80%, at least 85%, at least 90% at least 95%, or at least 100%.
 55. Themethod of any one of claims 21-26, 30-36, or 39-53, wherein the ME orformulation includes a water-soluble drug that reduces a symptom of IOP,glaucoma, AMD, uveitis, and/or conjunctivitis, by at most 10%, at most15%, at most 20%, at most 25%, at most 30%, at most 35%, at most 40%, atmost 45%, at most 50%, at most 55%, at most 60%, at most 65%, at most70%, at most 75%, at most 80%, at most 85%, at most 90%, at most 95% orat most 100%.
 56. The method of any one of claims 21-26, 30-36, or39-53, wherein the ME or formulation includes a water-soluble drug thatreduces a symptom of IOP, glaucoma, AMD, uveitis, and/or conjunctivitis,by about 10% to about 100%, about 10% to about 90%, about 10% to about80%, about 10% to about 70%, about 10% to about 60%, about 10% to about501, about 10% to about 40%, about 20% to about 100%, about 20% to about90%, about 20% to about 80%, about 20% to about 20%, about 20% to about60%, about 20% to about 50%, about 20% to about 40%, about 30% to about100%, about 30% to about 90%, about 30% to about 80%, about 30% to about70%, about 30% to about 60%, or about 30% to about 50%.
 57. The methodof any one of claims 21-26, 30-36, or 39-56, wherein the ME orformulation includes a therapeutically effective amount of awater-soluble drug in the range of about 0.3%/day to about 1.2%/day. 58.The method of any one of claims 21-26, 30-36, or 39-56, wherein the MEor formulation includes a therapeutically effective amount of awater-soluble drug in the range of at least 0.3% w/w/day, at least 0.4%w/w/day, at least 0.5% w/w/day, at least 0.6% w/w/day, at least 0.7%w/w/day, at least 0.8% w/w/day, at least 0.9% w/w/day, at least 1.0%w/w/day, at least 1.1% w/w/day, or at least 1.2% w/w/day.
 59. The methodof any one of claims 21-26, 30-36, or 39-56, wherein the ME orformulation includes a therapeutically effective amount of awater-soluble drug in the range of about 0.3% w/w/day to about 1.2%w/w/day, about 0.3% w/w/day to about 1.1% w/w/day, about 0.3% w/w/day toabout 1.0% w/w/day, about 0.3% w/w/day to about 0.9% w/w/day, about 0.3%w/w/day to about 0.8% w/w/day, about 0.4% w/w/day to about 1.2% w/w/day,about 0.4% w/w/day to about 1.1% w/w/day, about 0.4% w/w/day to about1.0% w/w/day, about 0.4% w/w/day to about 0.9% w/w/day, about 0.4%w/w/day to about 0.8% w/w/day, about 0.5% w/w/day to about 1.2% w/w/day,about 0.5% w/w/day to about 1.1% w/w/day, about 0.5% w/w/day to about1.0% w/w/day, about 0.5% w/w/day to about 0.9% w/w/day, about 0.5%w/w/day to about 0.8% w/w/day, about 0.55% w/w/day to about 1.2%w/w/day, about 0.55% w/w/day to about 1.1% w/w/day, about 0.55% w/w/dayto about 1.0% w/w/day, about 0.55% w/w/day to about 0.9% w/w/day, aboutor 0.55% w/w/day to about 0.8% w/w/day.
 60. The method of any one ofclaims 21-26, 30-36, or 39-59, wherein the ME or formulation isadministered as a single dose or is serially dosed.
 61. The method ofany one of claims 21-26, 30-36, or 39-60, wherein the ME or formulationis administered to a patient once daily, twice daily, trice daily, onceevery few days, or once weekly.
 62. The method of any one of claims21-26, 30-36, or 39-61, wherein the ME or formulation is administeredfor the treatment of IOP, glaucoma, AMD, uveitis, and/or conjunctivitisfor 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks,4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months,11 months, 12 months, or more.
 63. The method of any one of claims21-26, 30-36, or 39-62, wherein a therapeutically effective amount of awater-soluble drug reduces internal pressure within the eye of anindividual by at least 10%, at least 15%, at least 20%, at least 25%, atleast 30%, at least 35%, at least 40%, at least 45%, at least 50%, atleast 55%, at least 60%, at least 65%, at least 70%, at least 75%, atleast 80%, at least 85%, at least 90%, at least 95% or at least 100%.64. The method of any one of claims 21-26, 30-36, or 39-62, wherein atherapeutically effective amount of a water-soluble drug reducesinternal pressure within the eye of an individual by at most 10%, atmost 15%, at most 20%, at most 25%, at most 30%, at most 35%, at most40/o, at most 45%, at most 50%, at most 55%, at most 60%, at most 65%,at most 70%, at most 75%, at most 80%, at most 85%, at most 90%, at most95% or at most 100%.
 65. The method of any one of claims 21-26, 30-36,or 39-62, wherein a therapeutically effective amount of a water-solubledrug reduces internal pressure within the eye of an individual by about10% to about 100%, about 10% to about 90%, about 10% to about 80%, about10% to about 70%, about 10% to about 60%, about 10% to about 50%, about10% to about 40%, about 20% to about 100%, about 20% to about 90%, about20% to about 80%, about 20% to about 20%, about 20% to about 60%, about20% to about 50%, about 20% to about 40%, about 30% to about 100%, about30% to about 90%, about 30% to about 80%, about 30% to about 70%, about30% to about 60%, or about 30% to about 50%.